WO2024097856A1 - Biomarqueurs prédictifs pour la réactivité à des inhibiteurs de dpp dans des cancers - Google Patents
Biomarqueurs prédictifs pour la réactivité à des inhibiteurs de dpp dans des cancers Download PDFInfo
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- WO2024097856A1 WO2024097856A1 PCT/US2023/078486 US2023078486W WO2024097856A1 WO 2024097856 A1 WO2024097856 A1 WO 2024097856A1 US 2023078486 W US2023078486 W US 2023078486W WO 2024097856 A1 WO2024097856 A1 WO 2024097856A1
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
Definitions
- the present disclosure relates to compositions and methods for treating cancers and tumors by initial identification of potential biomarkers to predict the response to DPP inhibitors, particularly Talabostat or a pharmaceutically acceptable salt thereof, in subjects with hematological and/or solid cancers and subsequent treatment of such subjects using the compositions of the invention.
- the disclosure further relates to the identification and treatment of subjects that would likely respond to administration of a DPP inhibitor for treatment or enhancement of therapy in subjects with hematological and/or solid cancers.
- DPP dipeptidyl peptidase
- DPP8 and DPP9 initiate a pro-inflammatory form of cell death in macrophages called pyroptosis.
- Pyroptosis is typically initiated by a family of intracellular proteins called Nod-Like receptors (NLRs), which act as sensors for pathogen associated molecular patterns (PAMPs).
- NLRs Nod-Like receptors
- PAMPs pathogen associated molecular patterns
- DPP8/9 activates pyroptosis via the Nlrplb inflammasome in murine macrophages and CARD8 in human macrophages.
- DPP9 restrains NLRP1 activation and DPP9 inhibition leads to NLRP1 inflammasome activation.
- Induction of pyroptosis results in the liberation of IL-ip and IL-18 from macrophages and the consequent induction of a host of other cytokines (IL-6, G-CSF, IFN-y, etc.) that support subsequent immune activation.
- IL-6 IL-6, G-CSF, IFN-y, etc.
- DPP4 inhibition increases tumor content of CXCL9/10, which recruits CXCR3 + NK and T cells
- DPP8/9 inhibition activates the inflammasome followed by induction of immune cell pyroptosis, resulting in proinflammatory cytokine (such as IL- 18, IL-ip, TNFa, GM-CSF, and Eotaxin) release and stimulation of Thl response (IFNy, CCL2, IL-12 and IL-2). It is followed by dendritic cell (DC) activation further enhancing the CXCL9/10-CXCR3 axis. Activation of this axis results into tumor growth inhibition (Fitzgerald et al. J Immunother Cancer 2021, 9(11): e002837).
- DPP inhibitors have been demonstrated to generate significant clinical benefit for treating some cancers in some subjects, many subjects do not clinically respond to such inhibition (Eager et al., 2009b, Kelly et al., 1993). This creates a major obstacle to the effective treatment of many tumor types.
- the inventors of the present application evaluated the gene copy number of all the targets of Talabostat and mRNA expression of all the genes involved in the inflammasome pathway, and in the immune pathways in Talabostat responding and non-responding human leukemic cell lines.
- mRNA expression of a set of genes that have a differential expression in responding vs non-responding human leukemic cell lines and the copy number of DPP9 gene could be used as predictive biomarkers for the selection of patients with hematologic cancers (e.g. leukemia) and solid tumors/cancers for the treatment with DPP inhibitors, particularly Talabostat. These biomarkers would help to make clinical decisions resulting in improvements in the clinical outcome.
- the present disclosure provides methods of treating cancers and tumors by identifying and/or predicting the likelihood of response to treatment with a dipeptidyl Peptidase (DPP) inhibitor in subjects with a cancer/tumor, comprising measuring DNA copy number of DPP9 gene in the subject’s biological sample and administering an effective amount of a DPP inhibitor.
- DPP dipeptidyl Peptidase
- the DNA copy number of the DPP9 gene in a biological sample that is equal to or higher than a predetermined DPP9 gene threshold is indicative of likelihood that subject will respond favorably to DPP inhibitor.
- a method of treating a subject with a cancer using a dipeptidyl Peptidase (DPP) inhibitor comprising: a) obtaining a biological sample from the subject; b) measuring DNA copy number of a DPP9 gene in the biological sample and c) administering an effective amount of the DPP inhibitor to the subject if the DNA copy number of the DPP9 gene is equal to or higher than a predetermined DPP9 gene threshold.
- DPP dipeptidyl Peptidase
- the predetermined DPP9 gene threshold of DNA copy number is at least 10. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is at least 3.
- the predetermined DPP9 gene threshold of DNA copy number is about 3. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 13. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 12. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 11. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 10. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 9. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 8. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 7.
- the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 6. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 5. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 4. In embodiments, the predetermined DPP9 gene threshold of DNA copy number of DPP9 gene in the biological sample is determined to be about 3 to about 13. In embodiments, the predetermined DPP9 gene threshold of DNA copy number of DPP9 gene in the biological sample is determined to be about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13 or higher.
- a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor comprising: a) obtaining a biological sample from the subject; b) determining DNA copy number of DPP9 gene in the biological sample; and c) administering an effective amount of the DPP inhibitor to the subject if the DNA copy number of the DPP9 gene is equal to or higher than 3.
- DPP dipeptidyl peptidase
- the DNA copy number of DPP9 gene in the biological sample is determined to be from about 3 to about 13.
- the cancer is hematological cancer.
- the hematological cancer is selected from the group consisting of but not limited to leukemia, lymphoma or myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia or acute lymphocytic leukemia, acute myeloid leukemia (AML), Hodgkin and non-Hodgkin lymphoma.
- Chronic myelomonocytic leukemia Chronic neutrophilic leukemia, hairy cell leukemia, chronic idiopathic myelofibrosis, plasma cell leukemia; Heilmeyer-Schbner disease; panmyelosis; acute panmyelosis with myelofibrosis; lymphosarcoma cell leukemia; acute leukaemia of unspecified cell type; blastic phase chronic myelogenous leukemia; Stem cell leukemia; Chronic leukaemia of unspecified cell type; Subacute leukaemia of unspecified cell type; Accelerated phase chronic myelogenous leukemia; Polycythemia vera; Adult T-cell leukemia/lymphoma; Aggressive NK-cell leukemia; B-cell prolymphocytic leukemia; B-cell leukemia, Anaplastic large cell lymphoma; Angioimmunoblastic T-cell lymphoma; Hepatosplenic T-cell lymphoma; Folli
- the DPP inhibitor is DPP2/DPP4/DPP8/DPP9/FAP inhibitor.
- the DPP2/DPP4/DPP8/DPP9/FAP inhibitor is Talabostat or a pharmaceutically acceptable salt thereof, preferably Talabostat mesylate.
- a method for identifying and/or predicting the likelihood of response to treatment with dipeptidyl Peptidase (DPP) inhibitor in a subject with a cancer comprising: a) obtaining a biological sample from the subject; and b) determining DNA copy number of DPP9 gene in the biological sample; wherein a DNA copy number of DPP9 gene equal to or higher than a predetermined DPP9 gene threshold indicates that subject is likely to respond favorably to DPP inhibitor.
- DPP dipeptidyl Peptidase
- a method for identifying and/or predicting the likelihood of response to treatment with Talabostat or a pharmaceutically acceptable salt thereof in a subject with a hematological cancer comprises a) obtaining a biological sample from the subject and b) determining the DNA copy number of the DPP9 gene in the biological sample, wherein if the DNA copy number of DPP9 gene is equal to or higher than a predetermined DPP9 gene threshold, which. is indicative of likelihood that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof.
- the predetermined DPP9 gene threshold of DNA copy number is at least 3. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 13. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 12. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 11. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 10. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 9. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 8. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 7.
- the predetermined DPP9 gene threshold of DNA copy number. is between about 3 and about 6. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 5. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 4. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 3. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 4. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 5. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 6. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 7. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 8.
- the predetermined DPP9 gene threshold of DNA copy number. is about 9. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 10. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 11. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 12. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 13.
- the predetermined DPP9 gene threshold of DNA copy number is at least 3. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is about 3 to about 50. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or about 50.
- a method for identifying and/or predicting the likelihood of response to treatment with Talabostat or a pharmaceutically acceptable salt thereof in a subject with a hematological cancer comprises: a) obtaining a biological sample from the subject and b) determining the DNA copy number of DPP9 gene in the biological sample, wherein if the DNA copy number of DPP9 gene between about 3 and about 50, such value is indicative of likelihood that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof.
- the DNA copy number of DPP9 gene in the biological sample of the subject is determined to be about 3 to about 13.
- a method of treating a subject having or suspected of having a hematological cancer comprising: a) obtaining a biological sample from the subject; b) determining DNA copy number of DPP9 gene in the biological sample wherein if the DNA copy number of DPP9 gene is about 3 to about 13, such value is indicative of likelihood that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof; and c) administering an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof to the subject.
- the hematological cancer is acute myeloid leukemia.
- the disclosure encompasses methods of identifying and/or predicting the likelihood of response to treatment with dipeptidyl peptidase (DPP) inhibitor in subjects with solid tumors/cancers, comprising: measuring DNA copy number of DPP9 gene in the subject’s biological sample, and if the biological sample has a DNA copy number of the DPP9 gene of about 3 to about 13, such value is indicative of likelihood that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof, and administering an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof to the subject.
- DPP dipeptidyl peptidase
- the DPP inhibitor is a DPP2/DPP4/DPP8/DPP9/FAP inhibitor.
- the DPP2/DPP4/DPP8/DPP9/FAP inhibitor is Talabostat or a pharmaceutically acceptable salt thereof, preferably Talabostat mesylate.
- the disclosure provides a method of predicting the likelihood of response to treatment with Talabostat or a pharmaceutically acceptable salt thereof in subjects with solid tumor/cancer, comprising the steps of: a) obtaining a biological sample from the subject and b) determining DNA copy number of DPP9 gene in the biological sample; wherein if the DNA copy number of DPP9 gene is between about 3 and about 13 is indicative of likelihood that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof.
- a method of treating a subject having or suspected of having a solid tumor/cancer comprising: a) obtaining a biological sample from the subject; b) determining DNA copy number of DPP9 gene in the biological sample and c) administering an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof to the subject if the DNA copy number of the DPP9 gene is equal to or higher than a predetermined DPP9 gene threshold.
- the DNA copy number of DPP9 gene in the biological sample of the subject is determined to be about 2 to about 50.
- the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 13.
- DNA copy number of DPP9 gene in the biological sample of the subject is determined to be at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or higher.
- the DNA copy number of DPP9 gene is measured by RT-PCR, Multiplex ligation-dependent probe amplification (MLP A), Multiplex amplifiable probe hybridization (MAPH), Dynamic allele-specific hybridization (DASH), Comparative genomic hybridization (CGH), Oligonucleotides arrays, Genotype arrays or the like.
- MLP A Multiplex ligation-dependent probe amplification
- MAH Multiplex amplifiable probe hybridization
- DASH Dynamic allele-specific hybridization
- CGH Comparative genomic hybridization
- Oligonucleotides arrays Genotype arrays or the like.
- the determining the DNA copy number of DPP9 gene comprises performing an assay on the biological sample.
- the assay comprises PCR amplifying a gene and determining the DNA copy number.
- the hematologic cancer is selected from the group comprising of leukemia, lymphoma or myeloma.
- the leukemia includes chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myeloid leukemia or acute lymphocytic leukemia.
- the lymphoma includes both Hodgkin and nonHodgkin.
- the hematological cancer includes Chronic myelomonocytic leukemia, Chronic neutrophilic leukemia, hairy cell leukemia, chronic idiopathic myelofibrosis, plasma cell leukemia; Heilmeyer-Schbner disease; panmyelosis; acute panmyelosis with myelofibrosis; lymphosarcoma cell leukemia; acute leukaemia of unspecified cell type; blastic phase chronic myelogenous leukemia; Stem cell leukemia; Chronic leukaemia of unspecified cell type; Subacute leukaemia of unspecified cell type; Accelerated phase chronic myelogenous leukemia; Polycythemia vera; Adult T-cell leukemia/lymphoma; Aggressive NK-cell leukemia; B-cell prolymphocytic leukemia; B-cell leukemia, Anaplastic large cell lymphoma; Angioimmunoblastic T-cell lymphoma; Hepatosple
- the solid tumors/cancers are selected from the group comprising urogenital cancers (such as prostate cancers including small cell neuroendocrine prostate cancer; (SCNC), neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC) and adenocarcinoma type prostate cancer), renal cell cancer, bladder cancer), neuroendocrine cancer, thyroid cancer, colon cancer, kidney cancer, liver cancer, testicular cancer, vulvar cancer, wilm’s tumor, hormone sensitive or hormone refractory prostate cancer, gynecological cancers (such as ovarian cancer, cervical cancer, endometrial cancer, uterine cancer), lung cancer, non-small cell lung cancer, small cell lung cancer, gastrointestinal stromal cancers, gastrointestinal cancers (such as non-metastatic or metastatic colorectal cancers, pancreatic cancer, gastric cancer, oesophage
- SCNC small cell neuro
- the effective amount of Talabostat or a pharmaceutically acceptable salt thereof ranges from about 100 micrograms to about 800 micrograms, about 100 micrograms to about 600 micrograms (including about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 600 micrograms, about 700 micrograms, about 800 micrograms).
- the total daily dose of Talabostat or a pharmaceutically acceptable salt thereof is in the range of about 100 micrograms to about 50 mg, preferably about 100 mcg to about 10 mg, about 50 micrograms to about 3 mg, about 100 micrograms to about 2.5 mg, about 100 micrograms to about 2.0 mg.
- the dosing cycle of Talabostat comprises at least one administration cycle (e.g. 1, 2, 3, 4, 5, 6 or more cycles), and each treatment cycle is of about 21 days.
- Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
- the subject is administered Talabostat at a total daily dose of about 0.4 mg to about 0.6 mg.
- the dose of Talabostat or a pharmaceutically acceptable salt thereof is about 100 mcg, 200 mcg, 300 mcg, 400 mcg, 500 mcg, 600 mcg, 700 mcg, 800 mcg, 900 mcg, 1 mg, 1.1 mg 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, about 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.
- Talabostat or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 0.2 mg twice daily on day 1-7 of the first treatment cycle followed by about 0.3 mg twice daily on day 8-14 of the first treatment cycle.
- Talabostat or a pharmaceutically acceptable salt thereof may be administered at 0.3 mg as a morning dose and 0.3 mg as an evening dose.
- Talabostat mesylate is administered at a dose of about 0.4 mg in the morning and about 0.2 mg in the evening on Days 1 to 14 of a 21-day cycle. In embodiment, Talabostat mesylate is administered at a dose of about 0.2 mg in the morning and about 0.4 mg in the evening on Days 1 to 14 of a 21-day cycle. In embodiments Talabostat or a pharmaceutically acceptable salt thereof may be administered orally at a dose of about 0.2 mg thrice daily. [0043] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered with one or more active agents.
- the one or more active agents are selected from one or more checkpoint inhibitors, for example, CTLA-4 inhibitors, PD-1 inhibitors, PD-2 inhibitors, PD-L1 inhibitors, and PD-L2 inhibitors.
- Talabostat or a pharmaceutically acceptable salt thereof and the checkpoint inhibitors are administered concurrently, sequentially, or at a later time.
- one or more checkpoint inhibitors include pembrolizumab (Keytruda), ipilimumab (Yervoy), nivolumab (Opdivo) and atezolizumab (Tecentriq).
- the check point inhibitor is pembrolizumab.
- Pembrolizumab may be administered at a total dose of about 1 mg/kg to about 10 mg/kg, conveniently by injection (e.g., intravenously), most preferably as continuous infusion for 30 minutes.
- a suitable dose of Pembrolizumab administered intravenously may conveniently be from about 100 mg to about 500 mg.
- Pembrolizumab is administered intravenously at a total dose of about 200 mg.
- a single administration cycle comprises 21 days (21 -day cycle).
- Talabostat mesylate is administered orally at a dose of about 0.2 mg twice daily on day 1-7 of the first treatment cycle followed by about 0.3 mg twice daily on day 1-14 of the first treatment cycle plus pembrolizumab 200 mg administered intravenously (IV) on Day 1 every 21 days.
- the biological sample from the subject comprises nucleic acid molecules.
- a method of treating a subject having or suspected of having a hematologic cancer comprising (i) identifying the likelihood of subject with hematologic cancer to be responsive to the treatment with dipeptidyl Peptidase (DPP) inhibitor (e.g. Talabostat) and (ii) administering to the subject a therapeutically effective amount of the DPP inhibitor (e.g.
- DPP dipeptidyl Peptidase
- DPP9 when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30; DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30 as analysed by qRT-PCR.
- DPP dipeptidyl Peptidase
- DPP inhibitor e.g. Talabostat
- DPP9 in the range of about 0.1 to 25
- DPP8 in the range of about 0.05 to 2
- caspase 1 in the range of about 0.05 to 50
- CARD8 in the range of about 1 to 80
- PYCARD is in the range of 0.1 to 15 as analysed by qRT-PCR.
- a method of treating a subject having or suspected of having a hematologic cancer comprising (i) identifying the likelihood of subject with hematologic cancer to be responsive to the treatment with dipeptidyl peptidase (DPP) inhibitor (e.g. Talabostat) and (ii) administering to the subject a therapeutically effective amount of the DPP inhibitor (e.g.
- DPP dipeptidyl peptidase
- DPP9 in the range of about 0.7 to 22
- DPP8 in the range of about 0.4 to 3.6
- caspase 1 in the range of about 0.1 to 50
- CARD8 in the range of about 1.7 to 75
- PYCARD is in the range of 0.5 to 10.1 as analysed by qRT-PCR.
- a method of treating a subject having or suspected of having a hematologic cancer comprising (i) identifying the likelihood of subject with hematologic cancer to be responsive to the treatment with dipeptidyl peptidase (DPP) inhibitor (e.g. Talabostat) and (ii) administering to the subject a therapeutically effective amount of the DPP inhibitor (e.g.
- DPP dipeptidyl peptidase
- DPP9 in the range of about 1.4 to 22
- DPP8 in the range of about 0.5 to 3.6
- caspase 1 in the range of about 0.2 to 44
- CARD8 in the range of about 1.7 to 75
- PYCARD is in the range of 0.6 to 11 as analysed by qRT-PCR.
- an increased protein level of target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 indicates that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof.
- a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor comprising: a) obtaining a biological sample from the subject; b) determining level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene; and
- DPP inhibitor e.g. Talabostat
- DPP9 mRNA expression level of genes
- DPP9 is in the range of about 0.7 to about 30, DPP8 is in the range of about 0.4 to about 10
- caspase 1 is in the range of about 0.1 to about 60
- CARD8 in the range of about 1.7 to about 100
- PYCARD is in the range of about 0.5 to about 30
- AKT3 is in the range of about 0.02 to about 30
- CARD9 is in the range of about 0.004 to about 40
- CXCR4 is in the range of about 0.14 to about 150
- EPCAM is in the range of about 0.00 to about 10
- HLA-DMA is in the range of about 0.12 to about 10
- HLA-DRA is in the range of about 0.58 to about 100
- HLA-DRB3 is in the range of about 0.09 to about 30
- IL17RA is in the range of about 0.2 to about 50
- IL4R is in the range of about 0.03 to
- a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor comprising: a) obtaining a biological sample from the subject; b) determining level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene; an ⁇ (c) administering to the subject a therapeutically effective amount of the DPP inhibitor (e.g.
- DPP9 when the mRNA expression level of genes DPP9 is in the range of about 0.7 to about 25, DPP8 in the range of about 0.4 to about 5; caspase 1 is in the range of about 0.1 to about 50; CARD8 in the range of about 1.7 to about 80; PYCARD is in the range of about 0.5 to about 15; AKT3 is in the range of about 0.02 to about 15; CARD9 is in the range of about 0.004 to about 25; CXCR4 is in the range of about 0.14 to about 120; EPCAM is in the range of about 0.00 to about 2; HLA-DMA is in the range of about 0.12 to 5; HLA-DRA is in the range of about 0.58 to about 50; HLA-DRB3 is in the range of about 0.09 to about 15; IL17RA is in the range of about 0.2 to about 40; IL4R is in the range of about 0.03 to about 15; IL6R is in the range of about 1.18 to about 45; IRF8 is in the range of
- a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor comprising: a) obtaining a biological sample from the subject; b) determining level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene and (c ) administering to the subject a therapeutically effective amount of the DPP inhibitor (e.g.
- DPP9 when the mRNA expression level of genes DPP9 is in the range of about 0.7 to 22, DPP8 is in the range of about 0.4 to about 3.6; caspase 1 is in the range of about 0.1 to about 50; CARD8 is in the range of about 1.7 to about 80; PYCARD is in the range of 0.5 to about 10; AKT3 is in the range of about 0.02 to about 11.2; CARD9 is in the range of about 0.004 to about 23.3; CXCR4 is in the range of about 0.14 to about 114; EPC AM is in the range of about 0.00 to about 1.0; HLA-DMA is in the range of about 0.12 to about 2.7; HLA-DRA is in the range of about 0.58 to about 38.3; HLA-DRB3 is in the range of about 0.09 to about 11.1; IL17RA is in the range of about 0.2 to about 37.7; IL4R is in the range of about 0.03 to about 12.5; IL6R is in the range of about
- a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor comprising: a) obtaining a biological sample from the subject; b) determining level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene; and
- DPP inhibitor e.g. Talabostat
- DPP9 is in the range of about 1.4 to about 22
- DPP8 is in the range of about 0.5 to about 3.6
- caspase 1 is in the range of about 0.2 to about 44
- CARD8 is in the range of about 1.7 to about 75
- PYCARD is in the range of 0.6 to about 10
- AKT3 is in the range of about 0.02 to about 11.2
- CARD9 is in the range of about 0.8 to about 23.3
- CXCR4 is in the range of about 0.13 to about 114
- EPC AM is in the range of about 0 to about 0.65
- HLA-DMA is in the range of about 0.11 to about 2.7
- HLA- DRA is in the range of about 0.5 to about 39
- HLA-DRB3 is in the range of 0.07 to about 11.5
- IL17RA is in the range of about 0.4 to about 38
- IL4R is in the a therapeutically effective amount of the DPP
- an increase of about 2-1000-fold in expression level of one or more genes in a biological sample of the subject is indicative of likelihood that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels are relative to a subject who is non-responsive to therapy.
- a method of selecting the subjects with hematologic cancer who will respond favorably to treatment with a DPP inhibitor comprises assaying a biological sample from the subject for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA- DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to the HPRT1 gene.
- a method of selecting the subjects with solid tumors who will respond favorably to treatment with a DPP inhibitor e.g., Talabostat or a pharmaceutically acceptable salt thereof comprises assaying a biological sample from the subject for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene , and if the subject has an expression level of one of these genes as set forth herein, administering Talabostat or a pharmaceutically acceptable salt thereof and optionally one or more checkpoint inhibitors.
- a DPP inhibitor e.g., Talabostat or a pharmaceutically acceptable salt thereof
- a method of selecting the subjects with a hematologic cancer who will respond favorably to treatment with Talabostat or a pharmaceutically acceptable salt thereof comprises assaying a biological sample from the subject for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene.
- a method of selecting one or more subjects with a solid tumor/cancer who will respond favorably to treatment with Talabostat or a pharmaceutically acceptable salt thereof comprises: assaying a biological sample from the subject and determining the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA- DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to the HPRT1 gene.
- the expression levels for CARD8 relative to an HPRT1 gene are in the range of about 1.7 to about 100.
- the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for DPP8 are in the range of about 0.4 to about 10.
- the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for DPP9 are in the range of about 0.7 to about 30.
- the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for caspase-1 are in the range of about 0.1 to about 60. In embodiments, if the expression level for caspase-1 is in the range of about 0.05 to about 50, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for AKT3 are in the range of about 0.02 to about 30. In embodiments, if the expression level for AKT3 is in the range of about 0.01 to 15, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for CARD9 are in the range of about 0.004 to about 40. In embodiments, if the expression level for CARD9 is in the range of about 0.001 to about 30, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for CXCR4 are in the range of about 0.14 to about 150. In embodiments, if the expression levels for CXCR4 is in the range of about 0.05 to about 125, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for HLA-DMA are in the range of about 0.12 to about 10. In embodiments, if the expression level for HLA-DMA is in the range of about 0.05 to about 5, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for HLA-DRA are in the range of about 0.58 to about 100. In embodiments, if the expression level for HLA-DRA are in the range of about 0.50 to about 50, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for HLA-DRB3 are in the range of about 0.09 to about 30. In embodiments, if the expression level for HLA-DRB3 is in the range of about 0.09 to about 11.1, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for IL4R are in the range of about 0.03 to about 30. In embodiments, if the expression level for IL4R is in the range of about 0.01 to about 15, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for IL6R are in the range of about 1.18 to about 60. In embodiments, if the expression level for IL6R is in the range of about 1.2 to about 50, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for IRF8 are in the range of about 0.03 to about 60. In embodiments, if the expression level for IRF8 is in the range of about 0.01 to about 50, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for ITGB2 are in the range of about 6.5 to about 400. In embodiments, if the expression level for ITGB2 is in the range of about 5 to about 350, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for PSMB8 are in the range of about 3.0 to about 60. In embodiments, if the expression level for PSMB8 is in the range of about 1.0 to about 60, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- the expression levels for TARP are in the range of about 0.0001 to about 300. In embodiments, if the expression level for TARP is in the range of about 0.0001 to about 260, relative to the HPRT1 gene as analyzed, for example, by qRT-PCR, then the subject may exhibit a positive outcome and is eligible for treatment with Talabostat or a pharmaceutically acceptable salt thereof.
- a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor comprising 1) treatment of cancer after identifying a predetermined DPP9 gene threshold of DNA copy number of DPP9 gene; and (2) treatment after measuring the level of expression of one or more of the target genes and genes involved in immune pathways (e.g., DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2 TARP and PSMB8).
- DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2 TARP and PSMB8 e.g.
- a method of treating a subject with a hematological cancer using a dipeptidyl peptidase (DPP) inhibitor comprising 1) treatment of hematological cancer after identifying a predetermined DPP9 gene threshold of DNA copy number of DPP9 gene; and (2) treatment after measuring the level of expression of one or more of the target genes and genes involved in immune pathways (e.g., DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8).
- a method of treating a subject with a solid tumor/ cancer using a dipeptidyl peptidase (DPP) inhibitor comprising 1) treatment of solid tumor/ cancer after identifying a predetermined DPP9 gene threshold of DNA copy number of DPP9 gene; and (2) treatment after measuring the level of expression of one or more of the target genes and genes involved in immune pathways (e.g., DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8).
- determining the level of expression of one or more genes comprises performing an assay.
- the step of assaying the level of expression of one or more genes is performed by detecting gene expression, e.g., mRNA expression.
- the level of genes is determined by using any direct or indirect quantitative assay.
- the expression of one or more genes is measured at the mRNA level.
- the gene expression values, or levels are subjected to one or more transformation analyses, such as statistical analysis/transformation.
- the logistic regression analysis comprises: (i) adjusting the value of one or more of the gene expression values or levels by an appropriate weighting coefficient (e.g., regression coefficient) to produce a weighted score for each gene expression values or levels, and (ii) combining the weighted score for each gene expression values or levels to generate the predictive score (e.g. the likelihood that subject will respond to a DPP inhibitor or Talabostat treatment).
- an appropriate weighting coefficient e.g., regression coefficient
- the RNA expression is done using an immunoassay, immunohistochemistry, northern blotting, western blotting, in situ hybridization (ISH/FISH), a whole genomic sequencing, a whole proteomic sequencing, quantitative real-time polymerase chain reaction (q-RT-PCR) and RNA sequencing or mass spectrometry.
- the RNA expression is done using qRT-PCR.
- the biological sample is at least one body sample selected from the group consisting of a tissue, a cell, and a body fluid.
- the biological sample is tissue.
- the biological sample comprises nucleic acid molecule.
- the biological sample comprises blood, serum and plasma.
- present disclosure relates to a kit for detecting likelihood that a subject with a hematologic cancer will be responsive to treatment with one or more DPP inhibitors, comprising means/reagents for quantifying DNA copy number of DPP9 gene in a biological sample of the subject.
- present disclosure relates to a kit for detecting likelihood that a subject with a hematologic cancer will be responsive to treatment with a DPP inhibitors, comprising means/reagents for measuring expression of one or more target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 in a biological sample of the subject and comparing the levels of these genes relative to an HPRT1 gene.
- DPP9 DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 in a
- the DPP inhibitor is DPP2/DPP4/DPP8/DPP9/FAP inhibitor.
- the DPP2/DPP4/DPP8/DPP9/FAP inhibitor is Talabostat or a pharmaceutically acceptable salt thereof (preferably, Talabostat mesylate).
- the subject may optionally be treated with Talabostat or a pharmaceutically acceptable salt thereof in combination with a checkpoint inhibitor.
- Figure 1 comprising Figures la through Ik, is a series of images demonstrating the DNA copy number of DPPs and FAP genes in responding cell lines to Talabostat mesylate according to example 1.
- Figure 2 comprising Figures 2a through 2f, is a series of images demonstrating the DNA copy number of DPPs and FAP genes in nonresponding cell lines to Talabostat mesylate according to example 1.
- Figure 3 depicting the correlation of DPP9 copy number with percent cytotoxicity in responding and non-responding human leukemic cell lines after the administration of Talabostat mesylate according to example 1.
- Figure 4A depicting relative gene expression of 20 differentially expressed gene in responder (R) and non-responder (NR) human leukemic cell lines by nanostring technology (A-C) according to example 2. (Expression levels were normalized against HPRT1, a house keeping gene)
- Figure 4B depicting relative gene expression of 20 differentially expressed gene in responder (R) and non-responder (NR) human leukemic cell lines as confirmed by RT-PCR (A-C) according to example 2. (Expression levels were normalized against HPRT1, a house keeping gene)
- Figure 5 depicting relative gene expression of 20 differentially expressed gene in PBMCs from bone marrow of AML patients according to example 3.
- the qRT-PCR was utilized. (Expression levels were normalized against HPRT 1 , a house keeping gene).
- CARD8 Caspase recruitment domain (CARD)-containing protein
- DNA Deoxyribonucleic acid
- FAP Fibroblast activation protein
- IL interleukin
- MLPA Multiplex ligation-dependent probe amplification
- MPN myeloproliferative neoplasms
- MDS myelodysplastic syndrome
- NEPC neuroendocrine prostate cancer
- PAMPs pathogen associated molecular patterns
- qPCR quantitative polymerase chain reaction
- RNA Ribonucleic acid
- SCNC small cell neuroendocrine cancer
- predetermined DPP9 gene threshold refers to the copy number of the DPP9 gene in the biological samples obtained by examinations of subjects or samples collected from subjects.
- the predetermined threshold value can be an absolute value, a relative value, a value that has an upper or a lower limit, a range of values, an average value, a median value, a mean value, or a value as compared to a baseline value. It can be a threshold value or a range. It can be based on a large number of biological samples, such as from population of subjects of the chronological age matched group, or based on a pool of samples including or excluding the sample to be tested.
- DPP9 gene value in a biological sample is equal to or higher than the predetermined DPP9 gene threshold value, it is indicative that said subject has likelihood of getting favorable response from dipeptidyl peptidase inhibitor (e.g. Talabostat mesylate).
- dipeptidyl peptidase inhibitor e.g. Talabostat mesylate
- the terms “treat”, “treating” and “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
- the term “effective,” means adequate to accomplish a desired, expected, or intended result.
- a "therapeutically effective amount” as provided herein refers to an amount of a treatment necessary to provide the desired therapeutic effect, e.g., an amount that is effective to prevent, alleviate, or ameliorate symptoms of disease or condition or prolong the survival of the subject being treated.
- the disease or condition is cancer.
- the term “likelihood” generally refers to an increase in the probability of an event.
- the term “likelihood” when used in reference to the effectiveness of cancer response generally contemplates an increased probability that the rate of cancer progress or tumor cell growth will decrease.
- the term “likelihood” when used in reference to the effectiveness of a patient cancer response can also generally mean the increase of indicators, such as mRNA or protein expression, that may evidence an increase in the progress in treating the cancer.
- DPP dipeptidyl peptidase
- DPP gene classified under EC 3.4.14.
- DPP genes There are 9 types of DPP genes known to date. These include Cathepsin C (DPP-1), DPP-2, DPP-3, DPP-4, DPP-6, DPP-7, DPP-8, DPP-9 and DPP-10.
- the DPP also includes fibroblast activation protein (FAP).
- FAP fibroblast activation protein
- dipeptidyl peptidases and "DPP2/DPP4/DPP-8/DPP-9/FAP” refer to a subset of DPP enzymes or genes containing one or more of DPP-2, DPP-4, DPP-8, DPP-9 and/or FAP.
- dipeptidyl peptidase inhibitor used interchangeably also referred to herein as a “DPP inhibitor” or "DPP2/DPP4/DPP8/DPP9/FAP inhibitor”, is a compound that inhibits DPP2, DPP4, DPP8, DPP9 and/or FAP.
- the “copy number of a gene” or the “copy number of a biomarker” refers to the number of DNA sequences in a cell encoding a particular gene product. Generally, for a given gene, a mammal has two copies of each gene. As used herein copy numbers are determined for DPP genes. In embodiments, the copy number is determined for DPP9 gene.
- RNA includes mRNA transcripts, and/or specific spliced or other alternative variants of mRNA.
- protein refers to proteins translated from the RNA transcripts transcribed from the biomarkers.
- level of expression or “expression level” as used herein refers to a measurable level of expression of the products of biomarkers, (such as DPP9 gene). Higher expression or “higher level of expression” as used herein refers to (i) higher expression of the one or more genes (protein and/or mRNA) in one or more given cells present in the sample.
- test is used to refer to the act of identifying, screening, probing, testing measuring or determining, which act may be performed by any conventional means. For example, a sample may be assayed for the presence of a particular genetic marker by using a Northern blot.
- detecting means the act of extracting particular information from a given source, which may be direct or indirect.
- the presence of a given thing e.g., level of gene expression, etc. is detected in a biological sample.
- testing and "determining” contemplate a transformation of matter, e.g., a transformation of a biological sample, e.g., a tumor sample, from one state to another by means of subjecting that sample to physical testing.
- the term "obtaining” means to procure, e.g., to acquire possession of in any way, e.g., by physical intervention (e.g., biopsy) or non-physical intervention (e.g, transmittal of information via a server), etc.
- physical intervention e.g., biopsy
- non-physical intervention e.g., transmittal of information via a server
- selecting as used herein in reference to a patient is used to mean that a particular patient is specifically chosen from a larger group of patients on the basis of the particular patient having a predetermined criteria, e.g., the patient has an increase in the expression of one or more particular genes.
- predicting refers to that the methods described herein provide information to enable a health care provider to determine the likelihood that an individual having an increase in the expression of one or more particular genes will respond to or will respond more favorably to a given treatment.
- probe or “primer” is meant a single-stranded DNA or RNA molecule of defined sequence that can base-pair to a second DNA or RNA molecule that contains a complementary sequence (the “target”).
- target a complementary sequence
- the stability of the resulting hybrid depends upon the extent of the base-pairing that occurs.
- the extent of base-pairing is affected by parameters such as the degree of complementarity between the probe and target molecules and the degree of stringency of the hybridization conditions.
- the degree of hybridization stringency is affected by parameters such as temperature, salt concentration, and the concentration of organic molecules such as formamide, and is determined by methods known to one skilled in the art.
- Probes or primers specific for nucleic acids have at least 80%-90% sequence complementarity, preferably at least 91%-95% sequence complementarity, more preferably at least 96%-99% sequence complementarity, and most preferably 100% sequence complementarity to the region of the nucleic acid to which they hybridize.
- Probes, primers may be detectably-labeled, either radioactively, or non- radioactively, by methods well-known to those skilled in the art.
- Probes, primers, and oligonucleotides are used for methods involving nucleic acid hybridization, such as: nucleic acid sequencing, reverse transcription and/or nucleic acid amplification by the polymerase chain reaction, single stranded conformational polymorphism (SSCP) analysis, restriction fragment polymorphism (RFLP) analysis, Southern hybridization, Northern hybridization, in situ hybridization, electrophoretic mobility shift assay (EMSA).
- SSCP single stranded conformational polymorphism
- RFLP restriction fragment polymorphism
- Southern hybridization Southern hybridization
- Northern hybridization in situ hybridization
- ESA electrophoretic mobility shift assay
- sample encompass a variety of sample types obtained from a patient, individual, or subject and can be used in a diagnostic or monitoring assay.
- the patient sample may be obtained from a healthy subject or a patient having symptoms associated with or is suspected of having or likely to have or develop a disease or condition described herein.
- a sample obtained from a patient can be divided and only a portion may be used for diagnosis. Further, the sample, or a portion thereof, can be stored under conditions to maintain sample for later analysis.
- statically significant means that the alteration is greater than what might be expected to happen by chance alone.
- Statistical significance can be determined by any method known in the art. For example, statistical significance can be determined by p-value.
- the P-value is a measure of probability that a difference between groups during an experiment happened by chance. For example, a P-value of 0.01 means that there is a 1 in 100 chance the result occurred by chance. The lower the P-value, the more likely it is that the difference between groups was caused by, e.g., treatment. An alteration is considered to be statistically significant if the P-value is at least 0.05. Preferably, the P-value is 0.04, 0.03,0.02, 0.01, 0.005, 0.001 or less.
- Biomarker refers to a substance that is a distinctive indicator of a biological process, biological event and/or pathologic condition.
- DPP genes and other target genes and genes involved in immune pathways like caspase 1, CARD8 and PYCARD are the biomarkers for identifying the likelihood of cancer responsiveness to DPP inhibitors.
- the predictive biomarkers are used to assess the probability that a patient will respond to or benefit from a particular treatment.
- nucleic acid is meant any nucleic acid, whether composed of deoxyribonucleosides or ribonucleosides, and whether composed of phosphodiester linkages or modified linkages such as phosphotriester, phosphoramidate, siloxane, carbonate, carboxymethylester, acetamidate, carbamate, thioether, bridged phosphoramidate, bridged methylene phosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, bridged phosphorothioate or sulfone linkages, and combinations of such linkages.
- phosphodiester linkages or modified linkages such as phosphotriester, phosphoramidate, siloxane, carbonate, carboxymethylester, acetamidate, carbamate, thioether, bridged phosphoramidate, bridged methylene phosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, bridged phosphorot
- nucleic acid also specifically includes nucleic acids composed of bases other than the five biologically occurring bases (adenine, guanine, thymine, cytosine and uracil).
- nucleic acid typically refers to DNA and RNA.
- immune response includes T cell mediated and/or B cell mediated immune responses.
- exemplary immune responses include T cell responses, e.g., cytokine production and cellular cytotoxicity.
- immune response includes immune responses that are indirectly effected by T cell activation, e.g., antibody production (humoral responses) and activation of cytokine responsive cells, e.g., macrophages.
- cancer includes the decrease, limitation, or blockage, of for example a particular action, function, or interaction.
- cancer is “inhibited 1 if at least one symptom of the cancer is alleviated, terminated, slowed, or prevented.
- cancer is also “inhibited” if recurrence or metastasis of the cancer is reduced, slowed, delayed, or prevented.
- response 1 or “responsiveness” refers to an anti-cancer response, e.g. in the sense of reduction of tumor size or inhibiting tumor growth.
- the terms can also refer to an improved prognosis, for example, as reflected by an increased time to recurrence, which is the period to first recurrence censoring for second primary cancer as a first event or death without evidence of recurrence, or an increased overall survival, which is the period from treatment to death from any cause.
- To respond or to have a response means there is a beneficial endpoint attained when exposed to a stimulus. Alternatively, a negative or detrimental symptom is minimized, mitigated or attenuated on exposure to a stimulus. It will be appreciated that evaluating the likelihood that a tumor or subject will exhibit a favorable response is equivalent to evaluating the likelihood that the tumor or subject will not exhibit favorable response (i.e., will exhibit a lack of response or be non-responsive).
- cycle threshold or number refers to the PCR cycle number at which the fluorescence level passes a given set threshold level.
- the CT measurement can be used, for example, to approximate levels of mRNA in an original sample.
- the CT measurement is often used in terms of “dCT” or the “difference in the CT” score, when the CT of one nucleic acid is subtracted from the CT of another nucleic acid.
- the subject afflicted with different hematologic cancers for whom the likelihood of response to a DPP inhibitor therapy is determined is a mammal (e.g., mouse, rat, primate, non-human mammal, domestic animal such as dog, cat, cow, horse), and is preferably a human.
- a mammal e.g., mouse, rat, primate, non-human mammal, domestic animal such as dog, cat, cow, horse
- a human e.g., mouse, rat, primate, non-human mammal, domestic animal such as dog, cat, cow, horse
- the subject is afflicted with a solid tumor/cancer.
- the subject has not undergone any previous treatment, such as chemotherapy, radiation therapy, targeted therapy, and/or DPP9 inhibitor therapy.
- the subject has had surgery to remove cancerous or precancerous tissue.
- the subject has undergone previous treatment, such as chemotherapy, radiation therapy, and/or targeted therapy.
- the cancerous tissue has not been removed, e.g., the cancerous tissue may be located in an inoperable region of the body, such as in a tissue that is essential for life, or in a region where a surgical procedure would cause considerable risk of harm to the patient.
- the biological samples can be collected from a variety of sources from a patient including a body fluid sample, cell sample, or a tissue sample comprising nucleic acids and/or proteins.
- Body fluids' refer to fluids that are excreted or secreted from the body as well as fluids that are normally not (e.g., amniotic fluid, aqueous humor, bile, blood and blood plasma, cerebrospinal fluid, cerumen and earwax, cowper's fluid or pre-ejaculatory fluid, chyle, chyme, stool, female ejaculate, interstitial fluid, intracellular fluid, lymph, menses, breast milk, mucus, pleural fluid, pus, saliva, sebum semen, serum, Sweat, synovial fluid, tears, urine, vaginal lubrication, vitreous humor, vomit).
- the subject’s sample is selected from the group consisting of cells, cell lines, histological slides, paraffin embedded tissues, biopsies, whole blood, nipple aspirate, serum, plasma, buccal scrape, saliva, cerebrospinal fluid, urine, stool, and bone marrow.
- the sample is serum, plasma, tissue or urine.
- the sample is a tissue cell line.
- the sample comprises blood or serum.
- the samples can be collected from individuals repeatedly over a longitudinal period of time (e.g., once or more on the order of days, weeks, months, annually, biannually, etc.). Obtaining numerous samples from an individual over a period of time can be used to verify results from earlier detections and/or to identify an alteration in biological pattern as a result of for example, disease progression, drug treatment, etc. For example, subject samples can be taken and monitored every month, every two months, or combinations of one, two, or three months intervals according to the disclosure.
- the DPP and other pathway genes for e.g. CASPASE-1) amount and/or activity measurements of the subject obtained over time can be conveniently compared with each other, as well as with those of normal controls during the monitoring period, thereby providing the subjects own values, as an internal, or personal, control for long-term monitoring.
- DNA copy number of a biomarker in a sample from a subject is compared to a predetermined threshold value.
- the sample from the subject is typically from a diseased tissue, such as cancer cells or tissues.
- the DNA copy number of a biomarker from a subject is compared to a pre-determined level. This pre-determined level is typically obtained from normal samples.
- DNA copy number of a biomarker preferably the biomarker is DPP9 gene may be selected for treatment, evaluate a response to an DPP9 inhibitor and/or evaluate a response to a combination DPP9 inhibitor therapy.
- a predetermined DNA copy number of a biomarker may be determined in populations of patients with or without cancer.
- the pre-determined DNA copy number of a biomarker can be a single number, equally applicable to every patient, or the pre-determined DNA copy number of a biomarker can vary according to specific subpopulations of patients, age, weight, height, and other factors of a subject.
- the predetermined DNA copy number of DPP biomarker can be obtained by any suitable standard.
- the pre-determined DNA copy number of DPP9 gene can be obtained from the human for whom a patient selection is being assessed.
- the pre-determined DNA copy number of DPP9 gene can be obtained from a previous assessment of the same patient in such a manner that the progress of the selection of the patient can be monitored over time.
- the detection of level of expression of one or more target gene(s) and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 can include detecting nucleic acid products (e.g., mRNA, etc.) and/or polypeptide products (e.g., expressed proteins) obtained from a biological sample.
- nucleic acid products e.g., mRNA, etc.
- polypeptide products e.g., expressed proteins
- Sample preparation and separation can involve any of the procedures, depending on the type of sample collected and/or analysis of gene measurement(s).
- the test sample of cells or tissue sample will be obtained from the subject with cancer by biopsy or surgical resection.
- a sample of cells, tissue, or fluid may be removed by needle aspiration biopsy.
- Such procedures include, by way of example only, concentration, dilution, adjustment of pH, removal of high abundance polypeptides (e.g., albumin, gamma globulin, and transferrin etc.), addition of preservatives and calibrants, addition of protease inhibitors, addition of denaturants, desalting of samples, concentration of sample proteins, extraction and purification of lipids.
- the expression profile can be performed on a biopsy taken from a subject such as fresh tissue, frozen tissue, tissue processed in formalin (FFPE) or other fixatives.
- the test sample of, for example tissue may also be stored or flash frozen and stored at -80°C. for later use.
- the biopsied tissue sample may also be fixed with a fixative, such as formaldehyde, paraformaldehyde, or acetic acid/ethanol.
- the fixed tissue sample may be embedded in wax (paraffin) or a plastic resin.
- the embedded tissue sample (or frozen tissue sample) may be cut into thin sections.
- Removal of undesired proteins from a sample can be achieved using high affinity reagents, high molecular weight filters, microcentrifugation and/or electrodialysis.
- High affinity reagents include antibodies or other reagents (e.g., aptamers) that selectively bind to high abundance proteins.
- Sample preparation could also include ion exchange chromatography, metal ion affinity chromatography, gel filtration, hydrophobic chromatography, chromate focusing, adsorption chromatography, isoelectric focusing and related techniques.
- Molecular weight filters include membranes that separate molecules on the basis of size and molecular weight. Such filters may further employ reverse osmosis, nanofiltration, ultrafiltration and microfiltration.
- Microcentrifugation is a method for removing undesired polypeptides from a sample.
- Microcentrifuges centrifuge a sample up to approximately 17,000 rpm. They are lightweight devices which are primarily used for short-time centrifugation of samples up to around 0.2- 2.0 mL.
- Microcentrifuges designed for high speed operation can reach up to 35000 rpm, giving RCF up to 30000*g, and are called high-speed microcentrifuges.
- DNA can be isolated from a biological sample taken from a subject.
- DNA can be extracted and purified from biological samples using any suitable technique.
- a number of techniques for DNA extraction and/or purification are known in the art, and several are commercially available (e.g., ChargeSwitch®, MELTTM total nucleic acid isolation system, MagMAXTM FFPE total nucleic acid isolation kit, MagMAXTM total nucleic acid isolation kit, QIAamp DNA kit, Omni-PureTM genomic DNA purification system, WaterMasterTM DNA purification kit).
- Reagents such as DNAzoI® and TRI Reagent® can also be used to extract and/or purify DNA.
- DNA can be further purified using Proteinase K and/or RNAse.
- the DNA is isolated by DNeasy Blood and Tissue kit.
- RNA or protein may also be extracted from a fixed or wax-embedded tissue sample or a frozen tissue sample. Once a sample of cells or sample of tissue is removed from the subject with cancer, it may be processed for the isolation of RNA or protein using techniques well known in the art.
- nucleic acid molecules that correspond to biomarker nucleic acids that encode a biomarker polypeptide or a portion of such a polypeptide.
- nucleic acid molecule' is intended to include DNA molecules (e.g., cDNA or genomic DNA) and analogs of the DNA using nucleotide analogs.
- the nucleic acid molecule can be single-stranded or double-stranded, but preferably is double stranded DNA.
- An isolated nucleic acid molecule is one which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid molecule.
- an isolated nucleic acid molecule is free of sequences (preferably protein-encoding sequences) which naturally flank the nucleic acid (i.e., sequences located at the 5' and 3' ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived.
- a biomarker nucleic acid molecule of the present disclosure can be isolated using standard molecular biology techniques and the sequence information in the database records described herein. Using all or a portion of such nucleic acid sequences, nucleic acid molecules of the disclosure can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook et al., ed., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.,1989).
- a nucleic acid molecule of the disclosure can be amplified using cDNA, mRNA, or genomic DNA as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques.
- the nucleic acid molecules so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis.
- the nucleic acid or amplification product may be detected or quantified by hybridizing a labeled probe to a portion of the nucleic acid or amplified product and measuring the amount of probe/nucleic acid complexes using any suitable assay.
- the labeled probe comprises a detectable group that may be, for example, a fluorescent moiety, chemiluminescent moiety, radioisotope, biotin, avidin, enzyme, enzyme substrate, or other reactive group.
- detectable group may be, for example, a fluorescent moiety, chemiluminescent moiety, radioisotope, biotin, avidin, enzyme, enzyme substrate, or other reactive group.
- Other well-known detection techniques include, for example, gel filtration, gel electrophoresis and visualization of the amplicons, and High- Performance Liquid Chromatography (HPLC).
- the method comprises at least one of the following: obtaining or isolating mRNA from a sample from a subject, generating cDNA from the obtained mRNA, amplifying (specifically or non-specifically) the cDNA(s) corresponding to the one or more of the genes; and measuring the level of the cDNA(s), for example using a labelled oligonucleotide.
- the method comprises directly detecting mRNA levels (e.g., without generating/amplifying cDNA), for example using Northern blot, RNA Protection assay, DNA microarray (RPA) or any other method for direct mRNA quantification.
- the method comprises labeling the mRNA, for example using a fluorescent moiety, a chemiluminescent moiety, a radioisotope or any other suitable labeling moiety.
- Examples of methods to measure the amount/level of protein in a sample include, but are not limited to: Western blot, immunoblot, immunoassays such as enzyme immunoassays (EIA) such as enzyme multiplied immunoassay technique (EMIT), enzyme-linked immunosorbent assay (ELISA), antigen capture ELISA, sandwich ELISA, IgM antibody capture ELISA (MAC ELISA), microparticle enzyme immunoassay (MEIA); capillary electrophoresis immunoassays (CEIA); radioimmunoassays (RIA); immunoradiometric assays (IRMA); fluorescence polarization immunoassays (FPIA); and chemiluminescence assays (CL), immunoprecipitation, surface plasmon resonance (SPR), chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical (IHC) analysis, matrix- assisted laser desorption/ionization time-of-flight (MALDI-TOF
- the qPCR reactions herein are performed with 384-well platform ABL 7900H real-time qPCR system. CT values are calculated using qPCR.
- primers can be used to amplify a region of DNA of DPP gene.
- DPP gene that is used to determine DNA copy number is a single copy gene with low frequency of mutations and/or polymorphisms.
- the genes include DPP2, DPP4, DPP8, DPP9, FAP genes.
- the DPP gene is DPP9 gene.
- Biomarker nucleic acids and/or biomarker polypeptides can be analyzed according to the methods described herein and techniques known to the skilled artisan to identify such genetic or expression alterations useful for the present disclosure including, but not limited to, 1) an alteration in the level of a biomarker transcript or polypeptide, 2) a deletion or addition of one or more nucleotides from a biomarker gene, 3) a substitution of one or more nucleotides of a biomarker gene, 4) aberrant modification of a biomarker gene, such as an expression regulatory region, and the like.
- a biological sample is tested for the presence of copy number changes in genomic loci containing the genomic marker.
- a copy number of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 is predictive of likelihood of subject with hematological cancer or any solid tumor/cancer to be responsive to the treatment with dipeptidyl Peptidase (DPP) inhibitors.
- DPP dipeptidyl Peptidase
- the DNA copy number of the DPP9 gene in the biological sample equal to or higher than a predetermined DPP9 gene threshold is indicative of likelihood that subject will respond favorably to DPP inhibitor.
- the predetermined DPP9 gene threshold of DNA copy number. is at least about 3.
- the predetermined DPP9 gene threshold of DNA copy number. is between about 3 and about 13.
- the predetermined DPP9 gene threshold of DNA copy number. is between about 3 and about 12. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 11. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 10. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 9. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 8. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 7. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 6. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 5.
- the predetermined DPP9 gene threshold of DNA copy number. is between about 3 and about 4. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is about 3. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is about 4. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is about 5. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is about 6. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is about 7. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 8. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 9. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 10. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 11. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 12. In embodiments, the predetermined DPP9 gene threshold of DNA copy number.is about 13.
- Methods of evaluating the copy number of a biomarker locus include, but are not limited to, hybridization-based assays qPCR and next gen sequencing.
- the DNA copy number of DPP9 gene is measured by RT-PCR, Multiplex ligation-dependent probe amplification (MLP A), Multiplex amplifiable probe hybridization (MAPH), Dynamic allele-specific hybridization (DASH), Comparative genomic hybridization (CGH), Oligonucleotides arrays, Genotype arrays or the like.
- MLP A Multiplex ligation-dependent probe amplification
- MAH Multiplex amplifiable probe hybridization
- DASH Dynamic allele-specific hybridization
- CGH Comparative genomic hybridization
- Oligonucleotides arrays Genotype arrays or the like.
- DNA copy number of DPP9 gene could be used as a predictive biomarker for the selection of patients for the treatment with DPP inhibitors.
- the DPP inhibitor is Talabostat or a pharmaceutically acceptable salt thereof.
- the disclosure provides a method of identifying and/or predicting the likelihood of response to treatment with dipeptidyl Peptidase (DPP) inhibitor in subjects with a cancer, comprising measuring DNA copy number of DPP9 gene in the subject’s biological sample.
- the invention further encompasses administering a checkpoint inhibitor, for example, CTLA-4 inhibitors, PD-1 inhibitors, PD-2 inhibitors, PD-L1 inhibitors, and PD-L2 inhibitors.
- a checkpoint inhibitor for example, CTLA-4 inhibitors, PD-1 inhibitors, PD-2 inhibitors, PD-L1 inhibitors, and PD-L2 inhibitors.
- checkpoint inhibitors include pembrolizumab (Keytruda), ipilimumab (Yervoy), nivolumab (Opdivo) and atezolizumab (Tecentriq).
- the dipeptidyl Peptidase (DPP) inhibitor and the checkpoint inhibitor are administered concurrently, sequentially, or at a later time
- DNA copy number of the DPP9 gene in the biological sample equal to or higher than a predetermined DPP9 gene threshold is indicative of likelihood that subject will respond favorably to DPP inhibitor.
- a method of treating a subject with a cancer using a dipeptidyl Peptidase (DPP) inhibitor comprising: a) obtaining a biological sample from the subject; b) determining DNA copy number of DPP9 gene in the biological sample; and c) administering an effective amount of the DPP inhibitor to the subject if the DNA copy number of the DPP9 gene is equal to or higher than a predetermined DPP9 gene threshold.
- DPP dipeptidyl Peptidase
- the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 13.
- the predetermined DPP9 gene threshold of DNA copy number in the biological sample of the subject is about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12 or about 13.
- the cancer is a hematological cancer. In embodiments, the cancer is a solid tumor/cancer.
- a method of treating a subject having or suspected of having a hematological cancer comprising: a) obtaining a biological sample from the subject; b) determining DNA copy number of DPP9 gene in the biological sample and c) administering an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof to the subject if the DNA copy number of the DPP9 gene is equal to or higher than a predetermined DPP9 gene threshold.
- a method of treating a subject having or suspected of having acute myeloid leukemia comprising: a) obtaining a biological sample from the subject; b) determining DNA copy number of DPP9 gene in the biological sample and c) administering an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof to the subject if the DNA copy number of the DPP9 gene is equal to or higher than a predetermined DPP9 gene threshold.
- a method for identifying and/or predicting the likelihood of response to treatment with dipeptidyl Peptidase (DPP) inhibitor in a subject with a cancer comprises a) obtaining a biological sample from the subject; and b) measuring DNA copy number of DPP9 gene in the biological sample; wherein a DNA copy number of DPP9 gene equal to or higher than a predetermined DPP9 gene threshold indicates that subject is likely to respond favorably to DPP inhibitor.
- DPP dipeptidyl Peptidase
- a method for identifying and/or predicting the likelihood of response to treatment with Talabostat or a pharmaceutically acceptable salt thereof in a subject with a hematological cancer comprises a) obtaining a biological sample from the subject and b) determining DNA copy number of DPP9 gene in the biological sample; wherein if the DNA copy number of DPP9 gene is equal to or higher than a predetermined DPP9 gene threshold indicative of likelihood that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof.
- the predetermined DPP9 gene threshold is about 3. In embodiments, the predetermined DPP9 gene threshold of DNA copy number is between about 3 and about 13.
- the DNA copy number of DPP9 gene in the biological sample of the subject is determined to be about 3 or higher.
- the disclosure provides a method of identifying and/or predicting the likelihood of response to treatment with dipeptidyl Peptidase (DPP) inhibitor in subjects with solid tumor/cancer, comprising: measuring DNA copy number of DPP9 gene in the subject’s biological sample.
- DPP dipeptidyl Peptidase
- the disclosure provides a method of predicting the likelihood of response to treatment with Talabostat or a pharmaceutically acceptable salt thereof in subjects with solid tumor/cancer, comprising the steps of: a) obtaining a biological sample from the subject and b) determining DNA copy number of DPP9 gene in the biological sample; and c) comparing to a predetermined DPP9 gene threshold, wherein if the DNA copy number of DPP9 gene is equal to or higher than predetermined threshold is indicative of likelihood that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof.
- the disclosure provides method of treating a subject having or suspected of having a solid tumor/cancer, comprising a) obtaining a biological sample from the subject; b) determining the DNA copy number of DPP9 gene in the biological sample; and c) administering an effective amount of Talabostat or a pharmaceutically acceptable salt thereof to the subject if the DNA copy number of the DPP9 gene is equal to or higher than a predetermined DPP9 gene threshold.
- the predetermined DPP9 gene threshold of DNA copy number in the biological sample of the subject is determined to be between about 3 and about 13.
- the biological sample from the subject comprises nucleic acid molecules.
- the DNA copy number of DPP9 gene is measured by RT-PCR.
- the determining step comprises PCR amplifying a gene to determine the DNA copy number.
- the DPP inhibitor is DPP2/DPP4/DPP8/DPP9/FAP inhibitor.
- the DPP2/DPP4/DPP8/DPP9/FAP inhibitor is Talabostat or pharmaceutically acceptable salts thereof.
- the cancer is hematologic cancer.
- the hematological cancer is selected from the group consisting of leukemia, myeloma, lymphoma.
- the lymphoma includes both Hodgkin and non-Hodgkin.
- the leukemia includes acute myeloid leukemia.
- the hematological cancer includes Chronic myelomonocytic leukemia, Chronic neutrophilic leukemia, hairy cell leukemia, chronic idiopathic myelofibrosis, plasma cell leukemia; Heilmeyer-Schbner disease; panmyelosis; acute panmyelosis with myelofibrosis; lymphosarcoma cell leukemia; acute leukaemia of unspecified cell type; blastic phase chronic myelogenous leukemia; Stem cell leukemia; Chronic leukaemia of unspecified cell type; Subacute leukaemia of unspecified cell type; Accelerated phase chronic myelogenous leukemia; Polycythemia vera; Adult T-cell leukemia/lymphoma; Aggressive NK-cell leukemia; B-cell prolymphocytic leukemia; B-cell leukemia, Anaplastic large cell lymphoma; Angioimmunoblastic T-cell lymphoma; Hepatosple
- the solid tumor/cancer is selected from the group comprising urogenital cancers (such as prostate cancers including small cell neuroendocrine prostate cancer; (SCNC), neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC) and adenocarcinoma type prostate cancer, renal cell cancer, bladder cancer), neuroendocrine cancer, thyroid cancer, colon cancer, kidney cancer, liver cancer, testicular cancer, vulvar cancer, wilm's tumor, hormone sensitive or hormone refractory prostate cancer, gynecological cancers (such as ovarian cancer, cervical cancer, endometrial cancer, uterine cancer), lung cancer, non-small cell lung cancer, small cell lung cancer, gastrointestinal stromal cancers, gastrointestinal cancers (such as non-metastatic or metastatic colorectal cancers, pancreatic cancer, gastric cancer, oesophageal cancer
- the invention further encompasses administering a checkpoint inhibitor, for example, CTLA-4 inhibitors, PD-1 inhibitors, PD-2 inhibitors, PD-L1 inhibitors, and PD-L2 inhibitors.
- a checkpoint inhibitor for example, CTLA-4 inhibitors, PD-1 inhibitors, PD-2 inhibitors, PD-L1 inhibitors, and PD-L2 inhibitors.
- checkpoint inhibitors include pembrolizumab (Keytruda), ipilimumab (Yervoy), nivolumab (Opdivo) and atezolizumab (Tecentriq).
- the Talabostat or pharmaceutically acceptable salts thereof and the checkpoint inhibitor are administered concurrently, sequentially, or at a later time.
- a method of treating a subject having or suspected of having a hematologic cancer comprising (i) identifying the likelihood of subject with hematologic cancer to be responsive to the treatment with dipeptidyl peptidase (DPP) inhibitor (e.g. Talabostat or pharmaceutically acceptable salts thereof) and (ii) administering to the subject a therapeutically effective amount of the DPP inhibitor (e.g.
- DPP dipeptidyl peptidase
- DPP9 in the range of about 0.7 to about 30
- DPP8 in the range of about 0.4 to about 10
- caspase 1 in the range of about 0.1 to about 60
- CARD8 in the range of about 1.7 to about 100
- PYCARD is in the range of about 0.5 to about 30.
- a method of treating a subject having or suspected of having a hematologic cancer comprising (i) identifying the likelihood of subject with hematologic cancer to be responsive to the treatment with dipeptidyl Peptidase (DPP) inhibitor (e.g. Talabostat) and (ii) administering to the subject a therapeutically effective amount of the DPP inhibitor (e.g.
- DPP dipeptidyl Peptidase
- DPP9 in the range of about 0.7 to 22
- DPP8 in the range of about 0.4 to 3.6
- caspase 1 in the range of about 0.1 to 50
- CARD8 in the range of about 1.7 to 75
- PYCARD is in the range of 0.5 to 10 as analysed by qRT-PCR.
- a method of treating a subject having or suspected of having a hematologic cancer comprising (i) identifying the likelihood of subject with hematologic cancer to be responsive to the treatment with dipeptidyl peptidase (DPP) inhibitor (e.g. Talabostat) and (ii) administering to the subject a therapeutically effective amount of the DPP inhibitor (e.g.
- DPP dipeptidyl peptidase
- DPP9 in the range of about 1.4 to 22
- DPP8 in the range of about 0.5 to 3.6
- caspase 1 in the range of about 0.2 to 44
- CARD8 in the range of about 1.7 to 75
- PYCARD is in the range of 0.6 to 10 as analysed by qRT-PCR.
- an increased protein level of target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 indicates that subject will respond favorably to Talabostat.
- a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor comprising: a) obtaining a biological sample from the subject; b) determining level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene; and
- DPP inhibitor e.g. Talabostat
- DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10
- caspase 1 in the range of about 0.1 to about 60
- CARD8 in the range of about 1.7 to about 100
- PYCARD is in the range of about 0.5 to about 30
- AKT3 is in the range of about 0.02 to about 30
- CARD9 is in the range of about 0.004 to about 40
- CXCR4 is in the range of about 0.14 to about 150
- EPC AM is in the range of about 0.00 to about 10
- HLA-DMA is in the range of about 0.12 to about 10
- HLA-DRA is in the range of about 0.58 to about 100
- HLA-DRB3 is in the range of about 0.09 to about 30
- IL17RA is in the range of about 0.2 to about 50
- IL4R is in the
- a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor comprising: a) obtaining a biological sample from the subject; b) determining level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene; and
- DPP inhibitor e.g. Talabostat
- DPP inhibitor e.g. Talabostat
- caspase 1 in the range of about 0.1 to about 50
- CARD8 in the range of about 1.7 to about 80
- PYCARD is in the range of about 0.5 to about 15
- AKT3 is in the range of about 0.02 to about 15
- CARD9 is in the range of about 0.004 to about 25
- CXCR4 is in the range of about 0.14 to about 120
- EPCAM is in the range of about 0.00 to about 2
- HLA-DMA is in the range of about 0.12 to 5
- HLA- DRA is in the range of about 0.58 to about 50
- HLA-DRB3 is in the range of about 0.09 to about 15
- IL17RA is in the range of about 0.2 to about 40
- IL4R is in the range of about 0.03 to about 15
- IL17RA is in the range of about 0.2 to about 40
- IL4R is in the range of about
- a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor comprising: a) obtaining a biological sample from the subject; b) determining level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene; and
- DPP inhibitor e.g. Talabostat
- DPP inhibitor e.g. Talabostat
- caspase 1 in the range of about 0.1 to about 50,
- CARD8 in the range of about 1.7 to about 80
- PYCARD is in the range of 0.5 to about 10
- AKT3 is in the range of about 0.02 to about 11.2
- CARD9 is in the range of about 0.004 to about 23.3
- CXCR4 is in the range of about 0.14 to about 114
- EPC AM is in the range of about 0.00 to about 1.0
- HLA-DMA is in the range of about 0.12 to about 2.7
- HLA-DRA is in the range of about 0.58 to about 38.3
- HLA-DRB3 is in the range of about 0.09 to about 11.1
- IL17RA is in the range of about 0.2 to about 37.7
- IL4R is in
- a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor comprising: a) obtaining a biological sample from the subject; b) determining level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene; and
- DPP inhibitor e.g. Talabostat
- DPP inhibitor e.g. Talabostat
- DPP inhibitor e.g. Talabostat
- DPP9 mRNA expression level of genes DPP9 in the range of about 1.4 to about 22, DPP8 in the range of about 0.5 to about 3.6
- caspase 1 in the range of about 0.2 to about 44
- CARD8 in the range of about 1.7 to about 75
- PYCARD is in the range of 0.6 to about 10
- AKT3 is in the range of about 0.02 to about 11.2
- CARD9 is in the range of about 0.8 to about 23.3
- CXCR4 is in the range of about 0.13 to about 114
- EPC AM is in the range of about 0 to about 0.65
- HLA-DMA is in the range of about 0.11 to about 2.7
- HLA- DRA is in the range of about 0.5 to about 39
- HLA-DRB3 is in the range of 0.07 to about 11.5
- IL17RA
- a method of selecting the subjects with hematologic cancer who will respond favorably to treatment with a DPP inhibitor comprises assaying a biological sample from the subject for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA- DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene.
- a method of selecting the subjects with hematologic cancer who will respond favorably to treatment with Talabostat or a pharmaceutically acceptable salt thereof comprises assaying a biological sample from the subject for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRTl gene.
- a method of selecting the subjects with solid tumor/cancer who will respond favorably to treatment with a DPP inhibitor comprises assaying a biological sample from the subject for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA- DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene.
- a method of selecting the subjects with solid tumors who will respond favorably to treatment with Talabostat or a pharmaceutically acceptable salt thereof comprises: assaying a biological sample from the subject for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRTl gene.
- a method of treating a subject with a hematologic cancer using a DPP inhibitor or a pharmaceutically acceptable salt thereof comprises assaying a biological sample from the subject for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA- DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene; and administering an effective amount of the DPP inhibitor to the subject if the mRNA expression level of genes DPP9 is in the range of about 0.1 to 25, DPP8 is in the range of about 0.05 to 2, caspase-1 is in the range of about 0.05 to 50, CARD8 is in the range of about 1 to 80
- a method of treating a subject with a hematologic cancer using Talabostat or a pharmaceutically acceptable salt thereof comprises assaying a biological sample from the subject for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA- DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene and administering an effective amount of Talabostat or a pharmaceutically acceptable salt thereof to the subject if the mRNA expression level of genes DPP9 is in the range of about 0.1 to 25, DPP8 is in the range of about 0.05 to 2 caspase-1 is in the range of about 0.05 to 50, CARD8 is in the range of
- a method of treating a subject with a solid tumor/cancer using a DPP inhibitor comprising: a) assaying a biological sample from the subj ect for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA- DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene; and b) administering an effective amount of DPP inhibitor to the subj ect if the mRNA expression level of target genes and genes involved in immune pathways comprising DPP9 is in the range of about 0.1 to 25, DPP8 is in the range of about 0.05 to 2, caspase-1 is in the range of about
- a method of treating a subject with a solid tumor/cancer using Talabostat or a pharmaceutically acceptable salt thereof comprising: a) assaying a biological sample from the subj ect for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA- DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene; and b) administering an effective amount of Talabostat or a pharmaceutically acceptable salt thereof to the subject if the mRNA expression level of genes DPP9 is in the range of about 0.1 to 25, DPP8 is in the range of about 0.05 to 2 caspase-1 is in the range of about
- the invention further encompasses administering a checkpoint inhibitor, for example, CTLA-4 inhibitors, PD-1 inhibitors PD-2 inhibitors, PD-L1 inhibitors, and PD-L2 inhibitors.
- a checkpoint inhibitor for example, CTLA-4 inhibitors, PD-1 inhibitors PD-2 inhibitors, PD-L1 inhibitors, and PD-L2 inhibitors.
- checkpoint inhibitors include pembrolizumab (Keytruda), ipilimumab (Yervoy), nivolumab (Opdivo) and atezolizumab (Tecentriq).
- the Talabostat or pharmaceutically acceptable salts thereof and the checkpoint inhibitor are administered concurrently, sequentially, or at a later time.
- a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor comprising 1) treatment of cancer after identifying a predetermined DPP9 gene threshold of DNA copy number of DPP9 gene; and (2) treatment after measuring the level of expression of one or more of the target genes and genes involved in immune pathways (e.g., DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2 TARP and PSMB8).
- DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2 TARP and PSMB8 e.g.
- a method of treating a subject with a hematological cancer using a dipeptidyl peptidase (DPP) inhibitor comprising 1) treatment of hematological cancer after identifying a predetermined DPP9 gene threshold of DNA copy number of DPP9 gene; and (2) treatment after measuring the level of expression of one or more of the target genes and genes involved in immune pathways (e.g., DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2 TARP and PSMB8).
- a method of treating a subject with a solid tumor/ cancer using a dipeptidyl peptidase (DPP) inhibitor comprising 1) treatment of solid tumor/ cancer after identifying a predetermined DPP9 gene threshold of DNA copy number of DPP9 gene; and (2) treatment after measuring the level of expression of one or more of the target genes and genes involved in immune pathways (e.g., DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2 TARP and PSMB8).
- DPP inhibitor The likelihood of response to DPP inhibitor is predicted according to biomarker amount and/or activity associated with a hemotological cancer in a subject according to the methods described herein.
- DPP inhibitor can be administered once a subject is indicated as being a likely responder to DPP inhibitor.
- Combination therapies are also contemplated and can comprise, for example, one or more targeted agents, one or more chemotherapeutic agents and radiation, one or more chemotherapeutic agents and immunotherapy, or one or more chemotherapeutic agents, radiation and chemotherapy, each combination of which can be with DPP inhibitors.
- DPP inhibitors can be avoided once a subject is indicated as not being a likely responder to DPP inhibitor therapy and an alternative treatment regimen, such as targeted and/or untargeted anti-cancer therapies can be administered.
- the DPP inhibitor is DPP2/DPP4/DPP8/DPP9/FAP inhibitor.
- DPP2/DPP4/DPP8/DPP9/FAP inhibitor is Talabostat or a pharmaceutically acceptable salt thereof.
- dipeptidyl peptidase inhibitor is DPP2/DPP4/DPP8/DPP9/FAP inhibitor.
- DPP2/DPP4/DPP8/DPP9/FAP inhibitor is Talabostat (PubChem ID: 6918572), or a pharmaceutically acceptable salt thereof, such as, for example, Talabostat mesylate (PubChem CID: 1152248).
- Talabostat also known as PT-100 (Val-boro- pro; L- valinyl-L-boroproline), is disclosed in PCT Appl. Publication No. WO1989003223 (CAS registry number 149682- 77-9).
- the TUPAC name of Talabostat is [(2R)-l-[(2S)-2- amino-3- methylbutanoyl]pyrrolidin-2-yl]boronic acid.
- Talabostat has two chiral centers, and may be used as the free base or as a pharmaceutically acceptable salt, in any of its enantiomeric or diastereomeric forms, including mixtures thereof.
- Talabostat or a pharmaceutically acceptable salt thereof can also exist in both its non-cyclized and cyclic forms (RJ Snow et al., J. Am. Chem. Soc, 1994, 116 (24), pp 10860-10869).
- compositions include, for example, those prepared from typical inorganic acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like, as well as those prepared from organic acids, such as for example, aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyl alkandioic acids, aromatic acids, aliphatic (mesylate) and aromatic sulfonic acids, and any suitable form of Talabostat may be used in the combinations provided herein and the disclosure is not limited in this regard.
- a preferred salt form of Talabostat is the mesylate salt.
- Talabostat mesylate has a CAS registry number of 150080-09-4 and an IUPAC name as follows: [(2R)-l-[(2S)-2-amino-3- methylbutanoyl]pyrrolidin-2-yl]boronic acid; methanesulfonic acid.
- talabostat As well as talabostat-like compounds.
- Illustrative compounds encompass those described in at least the following documents.
- EP Patent No. 2,782,994 discloses talabostat analogs, such as, for example, ARI- 4175 and related compounds.
- PCT Appl. Publication No. W02003092605 discloses prodrugs of talabostat, such as, for example, cyclohexyl(glycinyl)-prolinyl-valinyl-L-boroproline.
- PCT Appl. Publication Nos. W02018049014 and W02018049008 disclose various compounds of the boro-pro class, and other dipeptides, and are herein referred to as talabostat-like boro-pro compounds.
- combination therapies include administering at least one additional therapeutic agent.
- An additional therapeutic agent can be administered prior to, concurrently with, and/or subsequently to, administration of the drug-targeting molecule conjugate.
- at least one additional therapeutic agent comprises 1, 2, 3, or more therapeutic agents.
- combination therapy comprises a therapeutic agent that affects the immune response (e.g., enhances or activates the response) and a therapeutic agent that affects (e.g., inhibits or kills) the tumor/cancer cells.
- a therapeutic agent that affects the immune response e.g., enhances or activates the response
- a therapeutic agent that affects e.g., inhibits or kills
- the dipeptidyl peptidase inhibitor (for example Talabostat) is administered in a dose of 0.001 mg/kg, 0.002 mg/kg, 0.003 mg/kg, 0.004 mg/kg, 0.005 mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg, 0.009 mg/kg, 0.010 mg/kg, 0.012 mg/kg, 0.013 mg/kg, 0.014 mg/kg, 0.020 mg/kg, 0.025 mg/kg, 0.030 mg/kg and 0.035 mg/kg.
- the dosage of the dipeptidyl peptidase inhibitor of the disclosure is a unit dose of about 0.001 mg/kg to about 10 mg/kg, 0.001 mg/kg to about 1 mg/kg, about 0.001 mg/kg to 0.05 mg/kg, about 0.001 mg/kg to 0.035 mg/kg, about 0.002 mg/kg to about 5 mg/kg, about 0.002 mg/kg to about 3 mg/kg, about 0.002 mg/kg to about 2 mg/kg, about 0.002 mg/kg to about 0.05 mg/kg, about 0.002 mg/kg to about 0.035 mg/kg, about 0.003 mg/kg to about 2.0mg/kg, about 0.003 mg/kg to about 2.0mg/kg, about 0.004 mg/kg to about 2.5 mg/kg, about 0.005 mg/kg to about 2.5 mg/kg, about 0.006 mg/kg to about 2.5 mg/kg, about 0.007 mg/kg to about 2.5 mg/kg, about 0.008 mg/kg to about
- the dose of Talabostat or a pharmaceutically acceptable salt thereof is about 100 mcg, 200 mcg, 300 mcg, 400 mcg, 500 mcg, 600 mcg, 700 mcg, 800 mcg, 900 mcg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, about 2mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.
- the dose of the Talabostat or a pharmaceutically acceptable salt there is administered one, two, three, four, five, six, seven, eight, nine or ten times per day.
- the effective amount of Talabostat or a pharmaceutically acceptable salt thereof ranges from about 100 micrograms to about 800 micrograms, about 100 micrograms to about 600 micrograms (including about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 700 micrograms)
- Total daily dose of dipeptidyl peptidase inhibitor may vary from about 100 mcg to 200 mg, preferably about 100 mcg to 50 mg, most preferably about 100 mcg to 10 mg.
- Total daily dose of Talabostat may vary from about 50 mcg to 3 mg, preferably about 100 mcg to 2.5 mg, most preferably about 100 mcg to 2.0 mg.
- the DPP inhibitor is administered twice a day, one dose per day, one dose every 2 days, one dose every 3 days, one dose every 4 days, one dose every 5 days, once a week, once every two weeks, or once every four weeks, preferably one dose per day.
- the dipeptidyl peptidase inhibitor is administered as a single dose, in two doses, in three doses, in four doses, in five doses, or in 6 or more doses.
- the dosing schedule can vary from e.g., once a day to once every 2, 3, or 4 weeks.
- the dipeptidyl peptidase inhibitor is administered at a dose from about 0.001 mg/kg to 3 mg/kg once a day.
- the dose frequency may vary from twice a day to once every month.
- the DPP inhibitor (or Talabostat) is administered as long as a clinical benefit is observed or until there is a complete response, confirmed progressive disease or unmanageable toxicity.
- a suitable daily dose of Talabostat or a pharmaceutically acceptable salt thereof administered orally via one or more (e.g. two or three) tablets in the present disclosure may conveniently be from about 0.1 mg to about 1 mg (e.g. about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, preferably about 0.1 mg to about 0.6 mg, more preferably about 0.4 mg to about 0.6 mg).
- Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
- the method comprising at least one administration cycle (e.g. 1, 2, 3, 4, 5, 6 or more cycles), and each treatment cycle is of about 21 days.
- the subject is administered Talabostat or a pharmaceutically acceptable salt thereof orally as tablets.
- the cycle is 21 days and Talabostat or a pharmaceutically acceptable salt thereof is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days where the patient takes no Talabostat.
- this intermittent dosing schedule occurs multiple times within the same cycle.
- said treatment is administered for at least 12 weeks, or at least 24 weeks.
- the patient achieves a complete response within 2-4 weeks after treatment.
- the subject treated with a single daily 0.6 mg dose of Talabostat mesylate does not experience dose-limiting side effects.
- Talabostat or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 0.2 mg twice daily on day 1-7 of the first treatment cycle followed by about 0.3 mg twice daily on day 8-14 of the first treatment cycle.
- each treatment cycle is of 21 -days duration and Talabostat or a pharmaceutically acceptable salt thereof is administered on each of days 1 to 14.
- Talabostat or a pharmaceutically acceptable salt thereof may be administered orally at a dose of about 0.3 mg twice daily in divided doses.
- Talabostat or a pharmaceutically acceptable salt thereof may be administered at 0.3 mg as a morning dose (e.g. about 5 am, about 6 am, about 7 am, about 8 am, about 9 am, about 10 am, or about 11 am) and 0.3 mg as an evening dose (e.g. about 5 pm, about 6 pm, about 7 pm, about 8 pm, about 9 pm, about 10 pm, or about 11 pm).
- a morning dose e.g. about 5 am, about 6 am, about 7 am, about 8 am, about 9 am, about 10 am, or about 11 am
- an evening dose e.g. about 5 pm, about 6 pm, about 7 pm, about 8 pm, about 9 pm, about 10 pm, or about 11 pm.
- Talabostat mesylate is administered at a dose of about 0.4 mg in the morning and about 0.2 mg in the evening on Days 1 to 14 of a 21-day cycle. In embodiment, Talabostat mesylate is administered at a dose of about 0.2 mg in the morning and about 0.4 mg in the evening on Days 1 to 14 of a 21-day cycle. In embodiments Talabostat or a pharmaceutically acceptable salt thereof may be administered orally at a dose of about 0.2 mg thrice daily.
- Talabostat or a pharmaceutically acceptable salt thereof is administered with one or more active agents selected from one or more checkpoint inhibitors, for example, CTLA-4 inhibitors, PD-1 inhibitors, PD-2 inhibitors, PD-L1 inhibitors, and PD- L2 inhibitors.
- active agents selected from one or more checkpoint inhibitors, for example, CTLA-4 inhibitors, PD-1 inhibitors, PD-2 inhibitors, PD-L1 inhibitors, and PD- L2 inhibitors.
- the check point inhibitor is pembrolizumab.
- Pembrolizumab may be administered at a total dose of about I mg/kg to about 10 mg/kg, conveniently by injection (e.g., intravenously), most preferably as continuous infusion for 30 minutes.
- a suitable dose of Pembrolizumab administered intravenously may conveniently be from about 100 mg to about 500 mg.
- Pembrolizumab is administered intravenously at a total dose of about 200 mg.
- a single administration cycle comprises 21 days (21 -day cycle).
- Talabostat mesylate is administered orally at a dose of about 0.2 mg twice daily on day 1-7 of the first treatment cycle followed by about 0.3 mg twice daily on day 1 to 14 of the first treatment cycle plus pembrolizumab 200 mg administered intravenously (IV) on Day 1 every 21 days.
- a suitable time period of therapy can be determined by one skilled in the art (e.g., a physician). As can be appreciated in the art, a suitable period of time can be determined by one skilled in the art based on one or more of: the stage of disease in the patient, the mass and sex of the patient, clinical trial guidelines (e.g., those on the fda.gov website), and information on the approved drug label.
- a suitable time period of therapy can be, e.g., from 1 week to 2 years, 1 week to 22 months, 1 week to 20 months, 1 week to 18 months, 1 week to 16 months, 1 week to 14 months, 1 week to 12 months, 1 week to 10 months, 1 week to 8 months, 1 week to 6 months, 1 week to 4 months 1 week to 2 months, 1 week to 1 month, 2 weeks to 2 years, 2 weeks to 22 months, 2 weeks to 20 months, 2 weeks to 18 months, 2 weeks to 16 months, 2 weeks to 14 months, 2 weeks to 12 months, 2 weeks to 10 months, 2 weeks to 8 months, 2 weeks to 6 months, 2 weeks to 4 months, 2 weeks to 2 months, 2 weeks to 1 month, 1 month to 2 years, 1 month to 22 months, 1 month to 20 months, 1 month to 18 months, 1 month to 16 months, 1 month to 14 months, 1 month to 12 months, 1 month to 10 months, 1 month to 8 months, 1 month to 6 months, 1 month to 4 months, 1 month to 2 months, 2 months to 2 years, 2 months to 22
- compositions of the present disclosure can be administered in any number of ways for either local or systemic treatment. Administration can be topical by epidermal or transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders; pulmonary by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal, and intranasal; oral; or parenteral including intravenous, intraarterial, intratumoral, subcutaneous, intraperitoneal, intramuscular (e.g., injection or infusion), or intracranial (e.g., intrathecal or intraventricular).
- parenteral including intravenous, intraarterial, intratumoral, subcutaneous, intraperitoneal, intramuscular (e.g., injection or infusion), or intracranial (e.g., intrathecal or intraventricular).
- the DPP inhibitors (e.g. Talabostat) of the present disclosure can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations.
- the present disclosure also provides pharmaceutical compositions including a pharmaceutically acceptable carrier or excipient and either a conjugate of the present disclosure, or a pharmaceutically acceptable salt of a compound of the present disclosure.
- a pharmaceutically acceptable carrier or excipient can be tailored to the particular composition and route of administration by methods well known in the art, e.g., REMINGTON’S PHARMACEUTICAL SCIENCES.
- compositions of DPP inhibitors can be either solid or liquid.
- Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington’s Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. (“Remington’s”).
- compositions can be in the form of various formulations such as tablets, capsules, emulsions, suspensions, solutions, syrups, sprays, lozenges, powders, and sustained-release formulations.
- Suitable excipients for oral administration include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
- the pharmaceutical formulations can be in unit dosage form.
- Such formulations include tablets, pills, capsules, powders, granules, solutions or suspensions in water or non-aqueous media, or suppositories.
- solid compositions such as tablets the active ingredient is mixed with a pharmaceutical carrier.
- Conventional tableting ingredients include a binder such as starch, com starch, polyvinylpyrrolidone, gums, gum acacia, gelatin, cellulose derivatives and the like; a diluent such as lactose, sucrose, sorbitol, dicalcium phosphate and the like; a lubricant such as talc, stearic acid, magnesium stearate and the like; and water.
- the solid preformulation composition is then subdivided into unit dosage forms of a type described above.
- the tablets, pills, etc. of the formulation or composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner composition covered by an outer component.
- the two components can be separated by an enteric layer that serves to resist disintegration and permits the inner component to pass intact through the stomach or to be delayed in release.
- a variety of materials can be used for such enteric layers or coatings, such materials include a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- the conjugates can also be formulated into a suppository disposed, for example, in a polyethylene glycol (PEG) carrier.
- PEG polyethylene glycol
- the present disclosure relates to a pharmaceutical composition of Talabostat for oral administration and process of preparing such formulation.
- Talabostat is formulated as an oral tablet.
- the pharmaceutical tablet may be an immediate release or a modified release tablet. Tablet may be in the form of matrix or coated form.
- the amount of Talabostat in a unit dose is about 100 micrograms per tablet, about 200 micrograms per tablet, about 300 micrograms per tablet, about 400 micrograms per tablet, about 500 micrograms per tablet, about 600 micrograms per tablet, about 700 micrograms per tablet, about 800 micrograms per tablet.
- DPP inhibitors described herein can also be entrapped in microcapsules.
- microcapsules are prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions as described in Remington: The Science and Practice of Pharmacy, 22. sup. nd Edition, 2012, Pharmaceutical Press, London.
- compositions include liposomes.
- Methods to produce liposomes are known to those of skill in the art. For example, some liposomes can be generated by reverse phase evaporation with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes can be extruded through filters of defined pore size to yield liposomes with the desired diameter.
- PEG-PE PEG-derivatized phosphatidylethanolamine
- sustained-release preparations comprising active drug (e.g. Talabostat) described herein can be produced.
- active drug e.g. Talabostat
- sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing a drug conjugate, where the matrices are in the form of shaped articles (e.g., films or microcapsules).
- sustained-release matrices include polyesters, hydrogels such as poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol), polylactides, copolymers of L- glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT. TM. (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3 -hydroxybutyric acid.
- polyesters such as poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)
- polylactides copolymers of L- glutamic acid and 7 ethyl-L-glutamate
- non-degradable ethylene-vinyl acetate non-degradable ethylene-vin
- Liquid compositions can be prepared by dissolving or dispersing an active drug and optionally one or more pharmaceutically acceptable adjuvants in a carrier such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension, e.g., for oral, topical, or intravenous administration.
- a carrier such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension, e.g., for oral, topical, or intravenous administration.
- compositions of the present disclosure can be in the form of emulsions, lotions, gels, creams, jellies, solutions, suspensions, ointments, and transdermal patches.
- the composition can be delivered as a dry powder or in liquid form via a nebulizer.
- the compositions can be in the form of sterile injectable solutions and sterile packaged powders.
- injectable solutions are formulated at a pH of about 4.5 to about 7.5.
- the compositions of the present disclosure can also be provided in a lyophilized form.
- compositions may include a buffer, e.g., bicarbonate, for reconstitution prior to administration, or the buffer may be included in the lyophilized composition for reconstitution with, e.g., water.
- the lyophilized composition can be provided in a syringe, optionally packaged in combination with the buffer for reconstitution, such that the reconstituted composition can be immediately administered to a patient.
- the dose administered will vary depending on a number of factors, including, but not limited to, the particular ligand or set of ligands to be administered, the mode of administration, the type of application (e.g., imaging, therapeutic), the age of the patient, and the physical condition (e.g. body surface area, weight, and physician assessment) of the patient.
- the smallest dose and concentration required to produce the desired result should be used.
- Dosage should be appropriately adjusted for children, the elderly, debilitated patients, and patients with cardiac and/or liver disease. Further guidance can be obtained from studies known in the art using experimental animal models for evaluating dosage. Suitable regimens can be selected by one skilled in the art by considering such factors and by following, for example, dosages reported in literature and recommended in the Physician’s Desk Reference (59 th ed., 2005).
- kits and compositions for carrying out the methods provided herein are also contemplated.
- kits useful for determining the likelihood of a subject with hemotological cancer to be responsive to the treatment with DPP inhibitor are also contemplated.
- kits useful for determining the likelihood of a subject with hemotological cancer to be responsive to the treatment with Talabostat are also contemplated.
- kits useful for determining the likelihood of a subject with solid tumor/cancer to be responsive to the treatment with DPP inhibitor are kits useful for determining the likelihood of a subject with solid tumor to be responsive to the treatment with Talabostat.
- kits for detecting whether a subject having a hematological cancer is sensitive to the treatment with a DPP inhibitor comprises means/reagents for quantifying DNA copy number of DPP9 gene in a sample of the subject.
- a kit for detecting whether a subject having a hematological cancer is sensitive to the treatment with a DPP inhibitor comprises means/reagents for measuring target gene and genes involved in immune pathways expression levels in a biological sample of the subject relative to an HPRT1 gene.
- kits for detecting whether a subject having a hematological cancer is sensitive to the treatment with Talabostat comprising means/reagents for measuring target gene expression levels in a biological sample of the subject.
- kits for detecting whether a subject having a solid tumor/cancer is sensitive to the treatment with Talabostat comprising means/reagents for measuring target gene expression levels in a biological sample of the subject.
- kits for detecting the DNA level of one or more biomarkers comprising one or more probes that bind specifically to the mRNAs of the one or more biomarkers.
- the kit further comprises a washing solution.
- the kit further comprises reagents for performing a hybridization assay, mRNA isolation or purification means, detection means, as well as positive and negative controls.
- the kit further comprises an instruction for using the kit.
- the kit can be tailored for in-home use, clinical use, or research use.
- the kit can additionally or optionally include reagents for assays capable of detecting the level of at least one biomarker, such as those needed for a colorimetric, fluorometric, or an enzymatic assay.
- the kit can additionally or optionally include reagents needed to detect the level of at least one biomarker using mass spectroscopy, such as internal standards and reagents (e.g., solvents) for separating and/or extracting biomarkers from a biological sample (e.g., using column chromatography).
- the kit can include an additional container having one or more components (e.g., a separation means, such as a chromatography column) when the kit is configured for detection of biomarkers using mass spectroscopy.
- kits to facilitate detection of at least one biomarker in a biological sample can include internal standards and solvents (e.g., chloroform/methanol) capable of extracting biomarkers from a biological sample, which are also compatible with mass spectroscopy.
- solvents e.g., chloroform/methanol
- kits can additionally or optionally include a biological sample collection means, such as a syringe, scalpel, swab, tweezers, or the like.
- kits provided herein employ means for detecting the expression of a biomarker by qPCR, microarray, or next gen sequencing.
- kits generally comprise pre-selected primers specific for particular nucleic acid sequences.
- the Quantitative PCR kits may also comprise enzymes suitable for amplifying nucleic acids (e.g., polymerases such as Taq), and deoxynucleotides and buffers needed for the reaction mixture for amplification.
- the Quantitative PCR kits may also comprise probes specific for the nucleic acid sequences associated with or indicative of a condition. The probes may or may not be labeled with a fluorophore. The probes may or may not be labeled with a quencher molecule.
- the quantitative PCR kits also comprise components suitable for reverse-transcribing RNA including enzymes (e.g., reverse transcriptases such as AMV, MMLV and the like) and primers for reverse transcription along with deoxynucleotides and buffers needed for the reverse transcription reaction.
- enzymes e.g., reverse transcriptases such as AMV, MMLV and the like
- primers for reverse transcription along with deoxynucleotides and buffers needed for the reverse transcription reaction.
- Each component of the quantitative PCR kit is generally in its own suitable container.
- these kits generally comprise distinct containers suitable for each individual reagent, enzyme, primer and probe.
- the quantitative PCR kits may comprise instructions for performing the assay and methods for interpreting and analyzing the data resulting from the performance of the assay.
- kits contain instructions for predicting whether a hematological cancer in a patient is clinically sensitive to a DPP inhibitor. In embodiments, the kits contain instructions for predicting whether a hematological cancer in a patient is clinically sensitive to Talabostat. In embodiments, the kits contain instructions for predicting whether a solid tumor in a patient is clinically sensitive to a DPP inhibitor. In embodiments, the kits contain instructions for predicting whether a solid tumor/cancer a patient is clinically sensitive to Talabostat.
- Embodiment 1 A method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor, the method comprising: a) obtaining a biological sample from the subject; b) determining DNA copy number of DPP9 gene in the biological sample and c) administering an effective amount of the DPP inhibitor to the subject if the DNA copy number of the DPP9 gene is equal to or higher than a predetermined DPP9 gene threshold.
- DPP dipeptidyl peptidase
- Embodiment 2 A method for identifying and/or predicting the likelihood of a response with dipeptidyl peptidase (DPP) inhibitor in a subject with a cancer, the method comprising: a) obtaining a biological sample from the subject;
- DPP dipeptidyl peptidase
- Embodiment 3 The method of embodiment 1 or 2, wherein the cancer is hematological cancer selected from the group consisting of leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia or acute lymphocytic leukemia.
- AML acute myeloid leukemia
- Hodgkin Hodgkin and non-Hodgkin lymphoma.
- Chronic myelomonocytic leukemia Chronic neutrophilic leukemia, hairy cell leukemia, chronic idiopathic myelofibrosis, plasma cell leukemia; Heilmeyer-Schbner disease; panmyelosis; acute panmyelosis with myelofibrosis; lymphosarcoma cell leukemia; acute leukaemia of unspecified cell type; blastic phase chronic myelogenous leukemia; Stem cell leukemia; Chronic leukaemia of unspecified cell type; Subacute leukaemia of unspecified cell type; Accelerated phase chronic myelogenous leukemia; Polycythemia vera; Adult T-cell leukemia/lymphoma; Aggressive NK-cell leukemia; B-cell prolymphocytic leukemia; B-cell leukemia, Anaplastic large cell lymphoma; Angioimmunoblastic T-cell lymphoma; Hepatosplenic T-cell lymphoma; Folli
- Embodiment 4 The method of embodiment 3, wherein the hematological cancer is acute myeloid leukemia.
- Embodiment 5 The method of embodiment 1, wherein the cancer is a solid tumor/cancer selected from the group consisting of urogenital cancers (such as prostate cancers including small cell neuroendocrine prostate cancer; (SCNC), neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC) and adenocarcinoma type prostate cancer), renal cell cancer, bladder cancer), neuroendocrine cancer, thyroid cancer, colon cancer, kidney cancer, liver cancer, testicular cancer, vulvar cancer, wilm’s tumor, hormone sensitive or hormone refractory prostate cancer, gynecological cancers (such as ovarian cancer, cervical cancer, endometrial cancer, uterine cancer), lung cancer, non-small cell lung cancer, small cell lung cancer, gastrointestinal stromal cancers, gastrointestinal cancers (such as non-metastatic or metastatic colorectal cancers, pancreatic cancer,
- Embodiment 6 The method of embodiment 1 or 2, wherein the DPP inhibitor is a DPP2/DPP4/DPP8/DPP9/FAP inhibitor.
- Embodiment 7. The method of embodiment 6, wherein the DPP2/DPP4/DPP8/DPP9/FAP inhibitor is Talabostat or a pharmaceutically acceptable salt thereof.
- Embodiment 8 The method of embodiment 7, wherein the DPP2/DPP4/DPP8/DPP9/FAP inhibitor is Talabostat mesylate.
- Embodiment 9 The method of embodiment 1 or 2, wherein the predetermined DPP9 gene threshold is about 3 or higher.
- Embodiment 10 The method of embodiment 1 or 2, wherein the predetermined DPP9 gene threshold is between 3 and 13.
- Embodiment 11 The method of embodiment 1 or 2, wherein the predetermined DPP9 gene threshold is between 2 and 13.
- Embodiment 12 The method of embodiment 1 or 2, wherein the predetermined DPP9 gene threshold is between 3 and 10.
- Embodiment 13 The method of embodiment 1 or 2, wherein the predetermined DPP9 gene threshold is between 3 and 6.
- Embodiment 14 The method of embodiment 1 or 2, wherein the predetermined DPP9 gene threshold is between 3 and 4.
- Embodiment 15 The method of embodiment 1 or 2, wherein the predetermined DPP9 gene threshold is about 3.
- Embodiment 16 The method of embodiment 1 or 7, wherein the effective amount of Talabostat or a pharmaceutically acceptable salt thereof ranges from about 100 mcg to about 1 mg.
- Embodiment 17 The method of embodiment 1 or 7, wherein the effective amount of Talabostat or a pharmaceutically acceptable salt thereof ranges from about 100 mcg to about 600 mcg.
- Embodiment 18 The method of embodiment 1 or 7, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.2 mg twice daily on one or more days of a treatment cycle.
- Embodiment 19 The method of embodiment 1 or 7, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
- Embodiment 20 The method of embodiment 1 or 2, wherein the assay is selected from quantitative polymerase chain reaction (qPCR) and next gen sequencing.
- qPCR quantitative polymerase chain reaction
- Embodiment 21 The method of embodiment 1 or 2, wherein the assay comprises PCR amplifying a gene and determining the DNA copy number of DPP9 gene.
- Embodiment 22 A method for identifying the likelihood of response to the treatment with Talabostat or a pharmaceutically acceptable salt thereof in a subject with a hematological cancer, wherein the method comprises a) obtaining a biological sample from the subject; and b) determining DNA copy number of DPP9 gene in the biological sample, wherein the DNA copy number of DPP9 gene equal to or higher than a predetermined DPP9 gene threshold is indicative of likelihood that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof.
- Embodiment 23 A method of treating a subject having or suspected of having a hematological cancer using Talabostat or a pharmaceutically acceptable salt thereof, the method comprising: a) obtaining a biological sample from the subject; b) determining the DNA copy number of DPP9 gene in the biological sample and c) administering an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof to the subject if the DNA copy number of the DPP9 gene is equal to or higher than a predetermined DPP9 gene threshold.
- Embodiment 24 The method of embodiment 22 or 23 wherein the predetermined DPP9 gene threshold is about 3.
- Embodiment 25 The method of embodiment 22 or 23, wherein the predetermined DPP9 gene threshold is between 3 to 13.
- Embodiment 26 The method of embodiment 22 or 23, wherein the predetermined DPP9 gene threshold is between 3 and 10.
- Embodiment 27 The method of embodiment 22 or 23, wherein the predetermined DPP9 gene threshold is between 3 and 6.
- Embodiment 28 The method of embodiment 22 or 23, wherein the predetermined DPP9 gene threshold is between 3 and 4.
- Embodiment 29 The method of embodiment 22 or 23, wherein the DNA copy number of DPP9 is determined using quantitative polymerase chain reaction (qPCR) and next gen sequencing.
- qPCR quantitative polymerase chain reaction
- Embodiment 30 The method of embodiment 22 or 23, wherein the DNA copy number of DPP9 is determined using PCR amplification of the gene.
- Embodiment 31 The method of embodiment 22 or 23 , wherein Talabostat or a pharmaceutically acceptable salt thereof is Talabostat mesylate salt.
- Embodiment 32 The method of embodiment 22 or 23, wherein the hematological cancer is selected from the group consisting of leukemia, lymphoma, myeloma, Chronic myelomonocytic leukemia, chronic neutrophilic leukemia, acute myeloid leukemia, hairy cell leukemia, chronic idiopathic myelofibrosis, plasma cell leukemia; Heilmeyer-Schbner disease; panmyelosis; acute panmyelosis with myelofibrosis; lymphosarcoma cell leukemia; acute leukaemia of unspecified cell type; blastic phase chronic myelogenous leukemia; Stem cell leukemia; Chronic leukaemia of unspecified cell type; Subacute leukaemia of unspecified cell type; Accelerated phase chronic myelogenous leukemia; Polycythemia vera; Adult T-cell leukemia/lymphoma; Aggressive NK-cell leukemia; B-cell pro
- Embodiment 33 The method of Embodiment 32, wherein the hematological cancer is acute myeloid leukemia.
- Embodiment 34 The method of Embodiment 22 or 23, wherein the biological sample comprises nucleic acid.
- Embodiment 35 The method of embodiments 22 or 23, further comprising administering at least one additional anti-cancer therapy.
- Embodiment 36 A method of predicting the likelihood of response to treatment with Talabostat or a pharmaceutically acceptable salt thereof in subjects with solid tumor/cancer, comprising the steps of: a) obtaining a biological sample from the subject and b) determining DNA copy number of DPP9 gene in the biological sample; wherein the DNA copy number of DPP9 gene equal to or higher than predetermined DPP9 gene threshold is indicative of likelihood that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof.
- Embodiment 37 A method of treating a subject having or suspected of having a solid tumor/cancer with Talabostat or a pharmaceutically acceptable salt thereof, the method comprising: a) obtaining a biological sample from the subject; b) determining DNA copy number of DPP9 gene in the biological sample; and c) administering an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof to the subject if the DNA copy number of the DPP9 gene is equal to or higher than a predetermined DPP9 gene threshold.
- Embodiment 38 The method of embodiment 36 or 37, wherein the predetermined DPP9 gene threshold of DNA copy number.is between about 3 and about 13.
- Embodiment 39 The method of embodiment 36 or 37, wherein the solid tumors/cancers are selected from the group comprising urogenital cancers (such as prostate cancers including small cell neuroendocrine prostate cancer; (SCNC), neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC) and adenocarcinoma type prostate cancer, renal cell cancer, bladder cancer), neuroendocrine cancer, thyroid cancer, colon cancer, kidney cancer, liver cancer, testicular cancer, vulvar cancer, wilm’s tumor, hormone sensitive or hormone refractory prostate cancer, gynecological cancers (such as ovarian cancer, cervical cancer, endometrial cancer, uterine cancer), lung cancer, non-small cell lung cancer, non-small cell lung
- Embodiment 40 The method of embodiment 36 or 37, wherein the Talabostat or a pharmaceutically acceptable salt thereof is Talabostat mesylate.
- Embodiment 41 A kit for detecting whether a subject having a cancer is sensitive to the treatment with a DPP inhibitor, wherein the kit comprising means/reagents for quantifying DNA copy number of DPP9 gene in a biological sample of the subject.
- Embodiment 42 A kit for detecting whether a subject having a cancer is sensitive to the treatment with a DPP inhibitor, wherein the kit comprising means/reagents for quantifying DNA copy number of DPP9 gene in a biological sample of the subject.
- a method of selecting the subjects with hematologic cancer who will respond favorably to treatment with a DPP inhibitor comprises assaying a biological sample from the subject for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA- DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene.
- Embodiment 43 A method of selecting the subjects with hematologic cancer who will respond favorably to treatment with Talabostat or a pharmaceutically acceptable salt thereof, the method comprises assaying a biological sample from the subject for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 and comparing the levels of these genes relative to an HPRT1 gene.
- the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, I
- Embodiment 44 A method of treating the subjects with hematological cancer who will respond favorably to treatment with Talabostat or a pharmaceutically acceptable salt thereof, the method comprises assaying a biological sample from the subject for the level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8; comparing the levels of these genes relative to an HPRT1 gene and administering a therapeutically effective amount of Talabostat or a pharmaceutically acceptable salt thereof.
- the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,H
- Embodiment 45 The method of embodiment 42 to 44, wherein the mRNA expression level of target genes and genes involved in immune pathways comprising DPP9 is in the range of about 0.7 to about 25, DPP8 is in the range of about 0.4 to about 5; caspase 1 is in the range of about 0.1 to about 50; CARD8 is in the range of about 1.7 to about 80; PYCARD is in the range of about 0.5 to about 15; AKT3 is in the range of about 0.02 to about 15; CARD9 is in the range of about 0.004 to about 25; CXCR4 is in the range of about 0.14 to about 120; EPCAM is in the range of about 0.00 to about 2; HLA-DMA is in the range of about 0.12 to 5; HLA-DRA is in the range of about 0.58 to about 50; HLA-DRB3 is in the range of about 0.09 to about 15; IL17RA is in the range of about 0.2 to about 40; IL4R is in the range of about 0.03 to about
- Embodiment 46 The method of embodiments 42 to 44, wherein the step of assaying the level of expression of one or more genes is performed by detecting gene expression, e.g., mRNA expression.
- Embodiment 47 The method of embodiments 42 to 44, wherein the level of one or more genes is determined by using any direct or indirect quantitative assay.
- Embodiment 48 The method of embodiment 42 to 44, wherein the gene expression values or levels are subjected to one or more transformation analyses, such as statistical analysis/transformation.
- Embodiment 49 A method of treating a subject having or suspected of having a hematologic cancer, comprising:
- DPP dipeptidyl peptidase
- a therapeutically effective amount of the DPP inhibitor e.g Talabostat
- DPP9, DPP8, caspase 1, CARD8 and PYCARD comprising DPP9 is in the range of about 0.7 to about 25
- DPP8 is in the range of about 0.4 to about 5
- caspase 1 is in the range of about 0.1 to about 50
- CARD8 is in the range of about 1.7 to about 80
- PYCARD is in the range of about 0.5 to about 15.
- Embodiment 50 The method of embodiment 49, wherein the assay is done using an immunoassay, immunohistochemistry, northern blotting, western blotting, in situ hybridization (ISH/FISH), a whole genomic sequencing, a whole proteomic sequencing, quantitative realtime polymerase chain reaction (q-RT-PCR) and RNA sequencing or mass spectrometry.
- immunoassay immunohistochemistry
- northern blotting northern blotting
- western blotting in situ hybridization
- ISH/FISH in situ hybridization
- q-RT-PCR quantitative realtime polymerase chain reaction
- RNA sequencing or mass spectrometry RNA sequencing or mass spectrometry.
- Embodiment 51 The method of embodiment 49, wherein the assay is done using qRT- PCR.
- Embodiment 52 The method of embodiment 49, wherein the biological sample is at least one body sample selected from the group consisting of a tissue, a cell, and a body fluid.
- Embodiment 53 The method of embodiment 49, wherein the hematologic cancer is selected from the group comprising of leukemia, lymphoma, myeloma, Chronic myelomonocytic leukemia, Chronic neutrophilic leukemia, hairy cell leukemia, acute myeloid leukemia, chronic idiopathic myelofibrosis, plasma cell leukemia; Heilmeyer-Schbner disease; panmyelosis; acute panmyelosis with myelofibrosis; lymphosarcoma cell leukemia; acute leukaemia of unspecified cell type; blastic phase chronic myelogenous leukemia; Stem cell leukemia; Chronic leukaemia of unspecified cell type; Subacute leukaemia of unspecified cell type; Accelerated
- Embodiment 54 The method of embodiment 49, wherein the cancer is Hodgkin’s or non-Hodgkin’s lymphoma.
- Embodiment 55 A kit for detecting likelihood of a subject with hematologic cancer to be responsive to the treatment with Talabostat or a pharmaceutically acceptable salt thereof, comprising means/reagents for measuring expression of one or more target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA,HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 in a biological sample of the subject comparing the levels of these genes relative to an HPRT1 gene
- Embodiment 56 The kit of embodiment 55, wherein Talabostat or a pharmaceutically acceptable salt thereof is Talabostat mesylate.
- Embodiment 57 The method or the kit of any of the preceding embodiments, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered orally.
- Embodiment 58 The method or kit of any of the preceding embodiments, wherein the total daily dose of Talabostat or a pharmaceutically acceptable salt thereof is in the range of about 100 micrograms to 10 micrograms, preferably about 100 mcg to 10 mg.
- Embodiment 59 The method or kit of any of the preceding embodiments, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered in form of tablets.
- Embodiment 60 The method or kit of any of the preceding embodiments, wherein the effective amount of Talabostat or a pharmaceutically acceptable salt thereof ranges from about 100 micrograms to about 800 micrograms.
- Embodiment 61 The method or kit of any of the preceding embodiments, wherein the effective amount of Talabostat or a pharmaceutically acceptable salt thereof ranges from about 100 micrograms to about 600 micrograms.
- Embodiment 62 The method or kit of any of the preceding embodiments, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 0.2 mg twice daily on day 1-7 of the first treatment cycle followed by about 0.3 mg twice daily on day 8-14 of the first treatment cycle.
- Embodiment 63 The method or kit of any of the preceding embodiments, wherein Talabostat or a pharmaceutically acceptable salt thereof may be administered at 0.3 mg as a morning dose and 0.3 mg as an evening dose.
- Embodiment 64 The method or kit of any of the preceding embodiments, wherein Talabostat mesylate is administered at a dose of about 0.4 mg in the morning and about 0.2 mg in the evening on Days 1 to 14 of a 21-day cycle.
- Embodiment 65 The method or kit of any of the preceding embodiments, wherein Talabostat mesylate is administered at a dose of about 0.2 mg in the morning and about 0.4 mg in the evening on Days 1 to 14 of a 21-day cycle.
- Embodiment 66 The method or kit of any of the preceding embodiments, wherein Talabostat or a pharmaceutically acceptable salt thereof may be administered orally at a dose of about 0.2 mg thrice daily.
- Embodiment 67 The method or kit of any of the preceding embodiments, wherein the subject is 18 years or older.
- Embodiment 68 The method or kit of any of the preceding embodiments, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered with one or more additional active agents.
- Embodiment 69 The methods or kit of embodiment 68, wherein the additional active agents are selected from one or more checkpoint inhibitors, for example, CTLA-4 inhibitors, PD-1 inhibitors, PD-2 inhibitors, PD-L1 inhibitors, and PD-L2 inhibitors.
- the additional active agents are selected from one or more checkpoint inhibitors, for example, CTLA-4 inhibitors, PD-1 inhibitors, PD-2 inhibitors, PD-L1 inhibitors, and PD-L2 inhibitors.
- Embodiment 70 The methods or kit of embodiment 68, wherein the checkpoint inhibitors include pembrolizumab (Keytruda), ipilimumab (Yervoy), nivolumab (Opdivo) and atezolizumab (Tecentriq).
- the checkpoint inhibitors include pembrolizumab (Keytruda), ipilimumab (Yervoy), nivolumab (Opdivo) and atezolizumab (Tecentriq).
- Embodiment 71 The methods or kit of embodiment 69 or 70, wherein the dipeptidyl Peptidase (DPP) inhibitor (e.g. Talabostat or a pharmaceutically acceptable salt thereof) and the checkpoint inhibitors are administered concurrently, sequentially, or at a later time.
- DPP dipeptidyl Peptidase
- Embodiment 72 The methods or kit of embodiment 71, wherein the checkpoint inhibitor is pembrolizumab.
- Embodiment 73 The methods or kit of embodiment 69 or 70, wherein the dipeptidyl Peptidase (DPP) inhibitor (e.g. Talabostat or a pharmaceutically acceptable salt thereof) is administered orally at a dose of about 0.2 mg twice daily on day 1-7 of the first treatment cycle followed by about 0.3 mg twice daily on day 1 to 14 of the first treatment cycle.
- DPP dipeptidyl Peptidase
- Embodiment 74 The methods or kit of embodiment 72, wherein Pembrolizumab is admi ni stered i ntraven ously .
- Embodiment 75 The methods or kit of embodiment 74, wherein Pembrolizumab is administered at a total dose of about 100 to 500 mg.
- Embodiment 76 The methods or kit of embodiment 74 or 75, wherein Pembrolizumab is administered intravenously at a total dose of about 200 mg.
- Embodiment 77 The methods or kit of embodiment 75, wherein pembrolizumab is administered at a dose of about 200 mg intravenously (IV) on Day 1 every 21 days.
- Embodiment 78 The methods or kits of any of preceding embodiments, wherein the single treatment cycle comprises of 21 days.
- EXAMPLE 1 To assay DPP8, DPP9, DPP4 and FAP genes DNA copy number in 17 human cell lines.
- DNA copy number in the cell lines were determined using multiplexed real time quantitative polymerase chain reaction (qPCR) utilizing ABI TaqMan chemistry (Applied Biosystems).
- Tissue was cut into small pieces up to 25 mg, and placed in a 1.5 ml microcentrifuge tube. Buffer ATL (180 pl) was added.
- Proteinase K (20 pl) was added, mixed thoroughly, and incubated at 56°C until the tissue was completely lysed. Vortexing was done occasionally during incubation to disperse the sample, or the sample was placed in a thermomixer, shaking water bath, or on a rocking platform.
- step 5 The mixture was pipetted from step 3 (including any precipitate) into the Dneasy Mini spin column placed in a 2 ml collection tube and centrifuged at 8000 rpm for 1 min. Discard flow-through.
- Dneasy Mini spin column was placed in a clean 1.5 ml or 2 ml microcentrifuge tube, and 200 pl Buffer AE was pipetted directly onto the Dneasy membrane. It was incubated at room temperature for 1 min, and then centrifuged for 1 min at 8000 rpm to elute.
- DNA quantification NanodropTM spectrophotometer detection (A260/A280). 2pl of cDNA of each sample was used for qPCR analysis in a total volume of lOpl reaction. Each sample was analyzed in triplicate. The qPCR reactions were performed with 384-well platform ABI-7900H real-time qPCR system using standard parameters suggested by the manufacturer. The CT values of the house-keeping gene are expected at a similar level.
- PCR amplification Each sample was diluted to 5 ng/pL with nuclease-free water. ) The PCR reaction system was set as follows in Table 5:
- Results are shown in table 9. It was observed that DPP9 gene copy number was correlated with the cytotoxicity of Talabostat in leukemic cell lines. Cell lines that were responding to Talabostat in a cytotoxicity assay had higher DPP9 gene copy number, and nonresponding cell lines had lower copy number. [0362] DPP9 gene copy number was highest amongst all genes evaluated. Interestingly, DPP9 gene copy number was the highest in responding cell lines and lowest in non-responding cell lines (figure 1 and 2). In all responding cell lines DPP9 gene copy number were more than four except in OCI-AML3. Although another variant of this cell line OCI-AML2 had a higher copy number. Six non-responsive cell lines had less than two DPP9 copy number.
- EXAMPLE 2 To measure the expression levels of a set of biomarker genes in responding and non- responding human leukemia cell lines using nanostring and RT-PCR techniques.
- the cytotoxic activity of Talabostat was evaluated in a panel of 170 hematological and non-hematological cell lines.
- gene expression analysis was done in different human leukemic cell lines by Nanostring. The absolute gene expression values were normalized against HPRT1, a house keeping gene, to provide relative gene expression for all the genes. Nanostring analysis was performed followed by qRT-PCR using cDNA from the cell lines.
- Cells grown in a monolayer in cell-culture vessels could be either lysed directly in the vessel (up to 10 cm diameter) or trypsinized and collected as a cell pellet prior to lysis. Cells grown in a monolayer in cell-culture flasks should always be trypsinized.
- the number of cells was determined.
- the cell-culture medium was completely aspirated, and proceeded immediately to step 2.
- the number of cells was determined. The medium was aspirated and the cells were washed with PBS.
- the PBS was aspirated and 0.10-0.25% trypsin added in PBS.
- the cell pellet was loosen thoroughly by flicking the tube.
- the appropriate volume of Buffer RLT Plus (see Table 11) was added. It was vortexed or pipeted to mix, and proceeded to step 3. Table 11. Volumes of Buffer RLT Plus for lysing pelleted cells
- Buffer RLT Plus For direct lysis of cells grown in a monolayer, the appropriate volume of Buffer RLT Plus (see Table 12) was added to the cell-culture dish. The lysate was collected with a rubber policeman.
- the lysate was pipetted into a microcentrifuge tube, vortexed or pipetted to mix and ensured that no cell clumps were visible before proceeding to step 3.
- the lysate was homogenized according to step 3a, 3b or 3c. If processing U1 x 105 cells, they can be homogenized by vortexing for 1 min. After homogenization, proceed to step
- lysate was passed at least 5 times through a 20-gauge needle (0.9 mm diameter) fitted to an RNase-free syringe. Proceed to step 4. 4. The homogenized lysate was transferred to an AllPrep DNA spin column placed in a 2 ml collection tube (supplied). The lid was closed gently, and centrifuged for 30 s at V8000 x g (VI 0,000 rpm).
- the AllPrep DNA spin column was placed in a new 2 ml collection tube (supplied), and stored at room temperature (15-25°C) or at 4°C for later DNA purification in steps 14-17. The flow-through was used for RNA purification in steps 6-13.
- sample volume exceeded 700 pl, successive aliquots were centrifuged in the same RNeasy spin column. Discard the flow-through after each centrifugation.
- Buffer RW 1 was added to the RNeasy spin column. The lid was closed gently, and centrifuge for 15 s at V8000 x g (VI 0,000 rpm) to wash the spin column membrane. Discard the flow-through.
- the long centrifugation dries the spin column membrane, ensuring that no ethanol was carried over during RNA elution. Residual ethanol may interfere with downstream reactions. 11.
- the RNeasy spin column was placed in a new 2 ml collection tube (supplied), and the old collection tube discarded with the flowthrough.
- This step was performed to eliminate any possible carryover of Buffer RPE, or if residual flowthrough remained on the outside of the RNeasy spin column after step 10.
- the RNeasy spin column was placed in a new 1.5 ml collection tube (supplied). 30-50 pl RNase-free water was added directly to the spin column membrane. The lid was closed gently, and centrifuged for 1 min at V8000 x g (VI 0,000 rpm) to elute the RNA.
- step 12 was repeated using another 30-50 pl of RNasefree water, or using the eluate from step 12 (if high RNA concentration was required). Reuse the collection tube from step 12.
- the RNA yield was 15-30% less than that obtained using a second volume of RNase-free water, but the final RNA concentration was higher.
- the working station was prepared by cleaning it with Sanihol, RNAse Away, and another layer of Sanihol.
- nCounter® 12 Well Notched Strip Tube was labelled with date and project name as well as appropriate set (for example: A,B,C, etc) and places on tube holder.
- the thermal cycler was programmed using the following settings: 65°C target temperature, 15 pL volume, 70°C lid temperature, for 18 hours and then ramped down to 4°C and hold.
- a program which has these specific settings has already been set up on the Applied Biosystems Proflex. The program is called “Nanostring 65”.
- the thermal cycler was preheated, the run was started and paused immediately when the heating block reached 65°C.
- RNA samples were thawed each sample was mixed by flicking the tube followed by a brief spin down in the centrifuge.
- RNA samples were placed on a cold block to avoid excessive RNA degradation and let thawed. Each tube was mixed by flicking followed by a brief spin in the table top centrifuge. (Refer to the “Nanostring Worksheet” to aliquot the appropriate amount of RNA into the strip tubes).
- RNA+water 7uL.
- the appropriate Reporter CodeSet was removed and the ProbeSet was captured from the -80°C and thawed at room temperature at working station. It was mixed by flicking or inverting the tubes and briefly spinned down in the mini centrifuge.
- a Hybridization Mastermix was made by adding 70pL of Hybridization Buffer [kept at room temperature (RT)] into the Reporter Code Set tube and mixed by flicking the tube and briefly spinned down.
- Capture ProbeSet was mixed by flicking and briefly spinning down. 2pL of the Capture ProbeSet was pipetted to each well, tips for each sample were changed and verified that capture Probeset was entirely added. The nCounter® Strip Tube was covered with a lid, spinned down to make sure Capture ProbeSet was added into the sample and not stuck on the wall of the tube. It was mixed by flicking the tube and spinned down again. It was made sure to minimize the time between the addition of the Capture ProbeSet and incubation at 65 °C.
- kit components were thawed on ice: a. 1 OX RT Buffer b. 25X dNTP Mix (100 mM) c. 10X RT Random Primers d. MultiScribe Reverse Transcriptase e. RNase Inhibitor
- RNA was normalized to 13.2 pL in nuclease-free water.
- Our standard RNA input amount was 200 ng for each 20 pL RT reaction. Up to 2 pg of RNA could be used per reaction with this kit.
- Each RT reaction would yield 20 pL of cDNA. Depending on number of replicates and probes running with it, multiple RT reactions per sample were set up and pooled them before qPCR.
- the RT master mix was created according to the table below.
- the tube was flicked to mix and quickly spinned down in a picofuge and kept on ice.
- the “Experimental Properties” sub-tab was selected in the left panel. a. The experiment was named and the project name was included and the date of run. b. “7500 (96 Wells)” as the instrument type was selected. c. “TaqMan Reagents” as the reagent type was selected. d. “Standard” ramp speed was selected e. The experiment was saved by clicking “Save As.” The filename reflected the name given to the experiment and could be saved as a Template.
- TaqMan probes and TaqMan Fast Advanced Master Mix (2X) were thawed on ice.
- a 125 pL VIAFLO was programmed to repeatedly dispense 17 pL.
- a 12.5 pL VIAFLO was programmed to repeatedly dispense 3 pL.
- the plate was sealed with an adhesive PCR plate seal.
- the plate was quick spinned to 1000 ref.
- the plate was placed inside of the 7500 instrument with well Al in the top left comer.
- Non-Res non-responding cell line to Talabostat
- Results The analysis identified 20 genes as potential predictive biomarkers. Twenty genes were found to be differentially expressed (transcripts levels) in rlonding (R) vs nonresponding (NR) human leukemic cell lines. Twenty genes are involved in the inflammasome pathway (including DPP9) and other immune signaling were found to be differentially expressed (transcripts levels) ilesponding (R) compared to non-responding (NR) human leukemic cell lines.
- RLT - lOpl P-ME per ml of RLT buffer was added just before use, stored at RT for upto one month. 350pl RLT (with PME) was used for cell numbers ⁇ 5 x 10 6. For cell numbers 5 x l0 6 - l x l0 7 use 600pl. If cell numbers were not known but a visible large pellet can be seen, 600pl of RLT was used.
- DNase I Stock 550 pl of the RNase-free water was added to the vial of DNAse I, mixed gently by inversion, Do not Vortex. It was stored in aliquots of 130pl or 65pl at -20°C.
- step 3.4 Repeated step 3.2 and 3.3 until all lysate was processed.
- Steps 3.12 and 3.13 were repeated and eluted into the same tube.
- Results Gene expression values were normalized against HPRT1, a house keeping gene.
- the data obtained from AML patients (Fig. 5 and Table 18) exhibit similar expression levels as that of responding and non-responding cell lines.
- the expression levels of 20 genes were low or high in various PBMCs samples from bone marrow of 10 AML patients.
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Abstract
La présente invention est basée sur l'identification du nombre de copies du gène DPP9 et l'expression d'un ensemble de gènes en tant que biomarqueurs prédictifs de la réactivité à des inhibiteurs de DPP, en particulier le talabostat ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également des méthodes de traitement de cancers hématologiques et de tumeurs solides.
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